It depends on what you are saying.
"You and me" works as an object (direct/indirect/ or object of preposition): The economic problems in the world might not be important to Bill Gates, but the make a difference to people like you and me.
"You and I" works as a subject: You are I are going shopping after work (whether you like it or not!).
Sometimes English speakers are trying so hard to be correct that they actually make mistakes with this and overgeneralize the use of "you and I".
I hope this helps.