I begin with a theme for the whole game. So I have one game set in a retro-futuristic setting (where I had to alter the decor and outfits of every single building and in built character), another which follows just one family, another which is a regular rotational game where every 7 game days a new character is moved in and another loosely based on the old Two Ronnies TV sketch "The Worm That Turned". I find the themes set the tone for each game.
Then I create the characters; I try not to make them all personality clones of each other, and then pitch them into the world! There's work/life balance, finding Mr or Mrs Right or at least Right Enough, working towards aspirations and trying to get enough money to buy those really big mansions. I tend not to micro manage my Sims and let needs and chance dictate play.
Right now, in the game set around just one family, the teenage son is finding it really hard trying to meet teenage girls. Older ladies seem to take a shine to him but he's waiting for a bunch of little girls he was at junior school with to age up. In the meantime he has to fend off all the old ladies and middle aged vamps.