Harnessing the patient’s immune system to control a tumor is a proven avenue for cancer therapy. T cell therapies as well as therapeutic vaccines, which target specific antigens of interest, are being explored as treatments in conjunction with immune checkpoint blockade. For these therapies, selecting the best suited antigens is crucial. Most of the focus has thus far been on neoantigens that arise from tumor-specific somatic mutations. Although there is clear evidence that T-cell responses against mutated neoantigens are protective, the large majority of these mutations are not immunogenic. In addition, most somatic mutations are unique to each individual patient and their targeting requires the development of individualized approaches. Therefore, novel antigen types are needed to broaden the scope of such treatments. We review high throughput approaches for discovering novel tumor antigens and some of the key challenges associated with their detection, and discuss considerations when selecting tumor antigens to target in the clinic.