Evaluation of tumor response is a vital element in clinical oncology research, particularly in the development of new drugs. Tumor response also plays a significant role in treatment decisions made by clinicians in practice. The underlying concept of tumor response, however, was developed as a result of limited understanding of tumor biology coupled with restricted availability of both effective treatments and imaging modalities. In recent years, impressive advances have been made in the treatment of cancer. Groundbreaking advances in our understanding of the molecular biology of tumor growth and proliferation have been made. New biologic agents have been approved for the treatment of several malignancies and, in many cases, biomarkers have been identified that can help predict those patients who will benefit. Pre-operative chemotherapy is now established for a number of tumor types. Modern imaging technologies allowing functional characterization of tumors have been introduced into clinical practice. In this new therapeutic landscape, the existing concept of tumor response risks becoming an anachronism, and revision of the criteria used to define tumor response is warranted. In this paper, we critically review the limitations of the classic criteria for tumor response assessment, and briefly discuss the potential role of alternative methodologies in providing a new, functional definition of tumor response.