In the past decade, basic studies in animal models have begun to elucidate the physiological barriers which impede a successful antitumor immune response. These barriers operate at a number of levels, and involve the tumor, the tumor microenvironment and various components of the innate and adaptive immune systems. In this review, we discuss the multiple mechanisms by which tumors evade an immune response, with an emphasis on clinically relevant strategies to overcome these inhibitory checkpoints.