Assessing the carcinogenic potential of innovative drugs spanning diverse therapeutic modalities and target biology represents a major challenge during drug development. Novel modalities, such as cell and gene therapies that involve intrinsic genetic modification of the host genome, require distinct approaches for identification of cancer hazard. We emphasize the need for customized weight of evidence cancer risk assessments based on mode of action that balance multiple options for preclinical identification of cancer hazard with appropriate labeling of clinical products and risk management plans. We review how advances in molecular carcinogenesis can enhance mechanistic interpretation and preclinical indicators of neoplasia, and recommend that drug targets be systematically assessed for potential association with tumorigenic phenotypes via genetic models and cancer genome resources