I base it on how big you want the player base to be, and what sort of stuff you want to include. As an example, when I built the grid for The Reach, we knew (or hoped anyway) it was going to be a big player base so that necessitated plenty of rooms. The grid's skeleton was sorta in place when I took over the pre-launch build so I left the street names intact and expanded outwards. Diversity of the environment was important, so I added swampy wilderness areas for a more rural character base, added some underground caves, expanded the cemetery, etc. Basically, I thought to myself, HiD/Gangrels need wilderness, Bone Shadows need cemeteries, etc. Financial/crime levels played into the design as well. We wanted some high crime, impoverished areas, and we wanted some wealthy areas.
As far as mapping goes, modeling after an existing city's general structure, then filling in the gaps with your custom content is a good way to go. You can search for things like "city-name neighborhoods" or "voting districts" or "crime rate map" to broadly divide the city into large chunks, then drill down from there.
The setting's geography plays a big role too in how you lay out the grid. So does the age of the city you're looking to copy/emulate.
GoogleEarth was helpful with some of the stuff I did on HM. Mozart sent me the Earth files with the grid breakdown and I could see how they'd separated everything based on the major streets.
