I have gone to ComicCon every year (sans one, which I will do a whole post about in a week or so) since '87. That's a lot of Cons. I know the routine pretty well by now, so I decided to spread my knowledge about. Probably most of this has been said elsewhere, so forgive me if you've read this before, but if you have, then you know I do not lie!
• Don't pack too tightly. Leave room in your bags for stuff. There will be stuff. You will come home with lots more than you came with. No matter what part of Con you are coming for, there will be things that you will acquire. You will buy things, you will be given things, you will get lots and lots of things. Make sure you can take them all home.
• Before you even get to Con check out their website. It has lots of info, but the most important thing it has is the schedule. You might even want to print it up. Read it thoroughly. Make sure you know when that panel that you want to go to more than anything is on. Look up the autograph schedule as well. Knowing when things are happening can make or break the whole weekend. Note: there will be things going on that are not mentioned in the guide. Booths have signings and events all the time that are not in the program. If there is something you really want to see, and you don't see a panel for it, check the website for whatever it is. Winter knows all about Avatar: The Last Airbender events that aren't on the schedule because she found them on the website.
• By now, this advice is likely too late, but, you should try to get to Con much earlier than the special omg thing you want to see. Be prepared that check-in will take a while. They get more efficient every year, and there are hordes of people working to get you in to the Con in a timely manner, but there are A LOT of people going to Con, and getting them all checked in takes time. Lines in the past have snaked around so far that you cannot see the end in the distance.
• If you are driving, my advice is to park your car somewhere cheap and leave it there. And be prepared to walk. Wear comfortable shoes. The exhibit hall itself is huge! I mean really really big. Just walking from one end to the other can exhaust you, and that's if the hall is empty which it never is. Getting around San Diego during Con, I find easier on foot. There are bus shuttles to hotels, trains, cabs, and these dreadful pedicabs everywhere, but for the most part, most places are an easy walk, and walking tends to be quicker. BUT WEAR COMFORTABLE SHOES.
• Everyday, as soon as you get to the convention center, the first things you should do is find the "On-Site Newsletter." THIS IS VERY IMPORTANT! They put one out every day and any changes in the schedule should be in there. Things that didn't make the schedule or got changed are all listed. The panel you are dying to see might have changed rooms or times, it's important to know what's going on.
• If you are on Twitter, this year, I would recommend checking it frequently, I know lots of people who plan on Tweeting about where they are during the weekend. You might get to see something special!
• If there is a panel you REALLY REALLY REALLY HAVE TO SEE, you probably want to get to the room early. Depending on what panels are going on, there are times when you could be waiting in a line for a panel you want to see, and not get into the room until way after it's over. The Con lets you stay in a room as long as you want, they even let you leave to use the bathroom and then get back in. If there is something that you can't miss, you probably want to camp out in the room until the panel. I have seen some very interesting panels that I only saw because I was waiting for something else (and have been very bored by others). There have been times when I have decided that I HAD to see a panel, so we got to the room very early, sat through all sorts of stuff, worked our way to the front, and managed to be in the front row. When talking to friends later, I found out that they had been in the panel as well. I had waited all day, they had not waited at all but they got in, but I was in the front row. Really depends on what's important to you. There have been other times that I have waited in long lines, only to be turned away because the room was filled and I was not early enough.
Hall H seats 6,500 and Ballroom 20 seats 4,500 or 5,000, something like that. That's a lot of people. It is easier to get into these rooms than the smaller rooms. That said, they do fill up, and there have been times that I got closed out of them. The smaller rooms fill up much faster.
• If you are with anyone, or hope to meet up with any friends, make sure that you all have cell phones, and make sure you know everyone's cell phone numbers. Keep your phone on vibrate (you're not likely to hear a ring in most places, and if it's quiet enough that you can hear the ring, chances are people will be very upset with you). As I mentioned above, the hall is huge, and there are many places people can be. In the old days, we would pick a spot and tell people to meet there, and then we would wait for hours and hours for whoever was missing. Today, everything is different. Cell phones rock. Especially the texting. Talking on a phone doesn't work well. Texting is better, you don't disturb anyone and you don't have to fight to hear.
Oh, and while I'm at it, just be aware that if you answer a phone while in the bathroom, everyone can hear everything you are saying. Just thought I mention that.
• For dinner, if you can, make reservations. Either that, or be prepared to wait for a really long time. Especially if you are in a big group. Long long time.
It's almost one in the morning, and I'm not sure if this was everything I had wanted to say. If I think of anything else, I will add it later.
I hope this helps.
ETA: Rather than me adding to this, people commenting on this post have great suggestions, so for more wonderful tips, read the comments!