Antibody-based drugs represent one of the most successful and promising therapeutic approaches in oncology. Large combinatorial phage antibody libraries are available for the identification of therapeutic antibodies and various technologies exist for their further conversion into multivalent and multispecific formats optimized for the desired pharmacokinetics and the pathological context. However, there is no technology for antigen profiling of intact tumors to identify tumor markers targetable with antibodies. Such constraints have led to a relative paucity of tumor-associated antigens for antibody targeting in oncology. Here we review novel approaches aimed at the identification of antibody-targetable, accessible antigens in intact tumors. We hope that such advanced selection approaches will be useful in the development of next-generation antibody therapies for cancer.