The rapid emergence of hundreds of new agents that modulate an ever-growing list of cancer-specific molecular targets offers tremendous hope for cancer patients. However, evaluating targeted agents individually, in combination with standard treatments, and in combination with other targeted agents presents significant development challenges. Because the number of possible drug combinations is essentially limitless, a strategy for determining the most promising combinations and prioritizing their evaluation is crucial. Here, we consider the crucial elements of a development strategy for targeted-agent combinations. Issues that pose challenges to the rational preclinical and clinical evaluation of such combinations will be described, and possible approaches to overcoming these challenges will be discussed.