Spot the Signs. Do you have a good relationship with your manager? Is he or she relatively reasonable? Do you have regular one_on_ones where you talk about your career goals and growth? If so, it's likely that your boss will accept your resignation with grace, help develop a plan of action for your last two weeks, and maybe even attend your farewell happy hour.
And sure, this could be an email (all of the same principles would apply), but a letter makes things official in every sense. It also gives you a prop to take along to the face_to_face meeting with your boss, when you let him or her know that you're leaving.