Standardized criteria for response to therapy in patients with chronic lymphocytic leukemia (CLL), lymphoma, and other malignancies allow for comparisons of outcome between clinical trials and have facilitated regulatory agency approval of novel active agents for use in current standard therapy. In 1988, the National Cancer Institute (NCI) Working Group published the first widely accepted criteria for CLL, 1 which were revised in 1996. 2 Such recommendations were developed in the context of currently available cytotoxic therapies. Later, in 2008, the International Workshop on CLL published criteria that incorporated much of the 1996 guidelines but also included guidance on how to assess minimal residual disease after therapy. 3 These published guidelines defined therapy outcome as either complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD), based on surrogate markers of tumor burden, such as blood lymphocyte count, lymph node size, or spleen size, and indicators of improved marrow function or clearance of leukemia cells from the marrow, as assessed by serial blood counts and/or marrow aspirate and biopsy. In general, these response criteria (CR, PR, SD, and PD) in therapeutic trials have correlated with the length of progression-free survival (PFS) and occasionally overall survival after treatment. Because assessment of response using these criteria can often be made years before survival data are available, response criteria have served as useful surrogate markers for assessing the clinical benefit of therapy, thereby accelerating the pace of approval of novel agents for use in the treatment of patients. Whereas the defined criteria of CR, PR, SD, and PD have helped to stratify patients into subgroups that correlate with PFS in many studies involving the use of traditional chemotherapy, it has recently become evident that these definitions may not faithfully predict outcome with newer agents under clinical investigation. In particular, the current definition of PD may not adequately serve as a surrogate marker for poor outcome, particularly for therapeutics that activate CLL B cells for subsequent immunologic destruction or generate an altered trafficking of B cells from different compartments to the blood. As a result, the Lymphoma Research Foundation sponsored a workshop in May 2011 to determine whether current response end points should be modified in light of the now well-recognized effects of such agents for treatment of patients with CLL. A brief description of therapeutic agents that highlight the confounding issues related to response assessment by current criteria is included, along with suggested changes to the guidelines that may assist in evaluating therapeutic benefit of these newer agents.