The main difference between creme brulee and panna cotta lies in their ingredients and preparation. Creme brulee is made with cream, egg yolks, and sugar, and is baked in a water bath until set. It's finished with a caramelized sugar topping. Panna cotta, on the other hand, is not baked but set by the addition of gelatin and chilled until firm. It lacks eggs and is not caramelized on top.