Significant scientific advances in biomedical research have expanded our knowledge of the molecular basis of carcinogenesis, mechanisms of cancer growth, and the importance of the cancer immunity cycle. However, despite scientific advances in the understanding of cancer biology, the success rate of oncology drug development remains the lowest among all therapeutic areas. In this review, some of the key translational drug development objectives in oncology will be outlined. The literature evidence of how mathematical modeling could be used to build a unifying framework to answer these questions will be summarized with recommendations on the strategies for building such a mathematical framework to facilitate the prediction of clinical efficacy and toxicity of investigational antineoplastic agents. Together, the literature evidence suggests that a rigorous and unifying preclinical to clinical translational framework based on mathematical models is extremely valuable for making go/no-go decisions in preclinical development, and for planning early clinical studies.