Updated: I posted line videos at the end, just to give you some sense of what to expect. Also: make sure you have your picture ID and confirmation print-out ready when you pick up your badge. No, they can't scan your phone - this is Comic Con, they are not that technically savvy. If you get up to bat and realize you forgot your print-out (truly a feeling of doom), you'll be sent to the Fedex counter and have to pay a fee to print it out there.
If you're staying around the convention center, Ralph's at 101 G Street is where you want to buy groceries. Consider keeping stuff like fruit, muffins or granola bars in your room because going out for breakfast every morning can eat up a lot of valuable time.
If you're lucky enough to have a Preview Night badge, show up early (say around 1:00, as opposed to the 3:00 time they tell you) and you can usually breeze right in and get badged, no line. Well, that was true in previous years, at least. Who knows what fresh hell will prevail this year. And though you'll see a line of hundreds of people waiting to get into the Exhibit Hall, you really don't need to join it - I've always picked up my badge, returned at 6 and gotten right in when they did.
If you have another kind of badge, do everything in your power to get in line early. If you have a 4-day or Thursday single day badge, you can pick it up at the Town and Country Wednesday - but last year this caused an epic traffic jam, so get there early. If you want to pick up your badge at the convention center, be aware that people line up very early. As in, during the night hours. I arrived for Thursday's pre-reg line at dawn last year and there was already a badge pick-up line opposite us that stretched from the convention center down to the Manchester Hyatt. Possibly farther.
I said this on my Restaurant page, but don't listen to the people who say eating at "Con classics" like Dick's Last Resort and other popular places is some kind of mandatory experience. They can be okay, but they're really crowded and you will get served faster at random places in the Gaslamp, down in Seaport Village or Little Italy, etc. Places I almost never have to wait: McCormack and Schmick's in the Omni, Blue Point Coastal, de Medici. Con attendees always think the "nice" restaurants are going to be too expensive but the prices aren't that different from mediocre places like the SyFy Cafe (which does usually stay open till 2 or 3 a.m., so it has its uses.) If you don't mind bar food, sometimes that is the fastest route to a full stomach.
Don't bring a lot of stuff - you need room to bring your plunder home with you. Don't bring (as I used to) six pairs of shoes and elaborate outfits for every occasion. All you will care about after the first day is being comfortable and reasonably clean.
Make sure you bring ibuprofen, comfortable shoes, bandaids for blisters, condoms, sunscreen, a bathing suit, business cards, batteries for your camera, a sketchbook, your chargers. If you get cold easily, bring something warm to wear at night.
Organize in advance, because you will be overwhelmed, mind blown, upon arrival. Use the CCI tool or make your own spreadsheet so you have a list of the panels you want to see and the booths you want to visit accessible on your phone. There's so much going on that even priorities will slip your mind, otherwise.
Get in touch with your long-distance friends now and make solid, definite plans to hang out. The chaos that is Comic Con tends to tear vague plans asunder.
Lastly - have you seen the convention center? Here's an aerial view. The big long facility in the middle is the convention center. You can see the Hilton Bayfront to your right, and that shiny mirrored-looking building to its left is the Marriott Marquis. So when you hear those hotels described as "adjacent," know that going from a panel in room 6BCF to the Indigo Ballroom at the Hilton is going to take a few minutes. Just something to keep in mind. The car size should provide a sense of perspective.
If you want to get an idea of how far Ballroom 20 is from Hall H or room 3, look at this map.
Good luck. :)
I'm posting a few videos just to give you some ideas on how long the lines really can be. And I'm going to repeat my advice - when you join the end of a long line, ask people what line it is, just to make sure you're in the right one. This is especially true in front of the convention center, where there are attendee lines, volunteer lines, professional lines, etc.
Sometimes you'll see a line so colossal you'll assume there's no chance of you ever getting in. That's not always true, particularly of Hall H. But be aware that the big rooms are not cleared after panels.
Town and Country Wednesday night, picking up badges:
Ballroom 20 line (don't listen to him when he says it's the largest room - it's not, Hall H is)
Masquerade Line 2009 - note the historical "Twilight ruined Comic Con" signs