Each year, millions of individuals undergo cancer surgery that is intended to be curative or at least a necessary component of a curative regimen. Particularly for those patients whose cancer harbors cells that are resistant to chemotherapy or radiation, the extent of surgery often defines whether they will be a survivor or casualty of the disease. For many solid tumor types, the difference in survival between patients who undergo gross total resection and those who have residual bulky disease is often profound. With surgery being central to cancer survivorship, it is stunning how few resources have been invested in improving surgical outcomes, particularly in comparison to chemotherapeutic research and discovery. This article reviews recent advances related to developing targeted fluorescent agents to guide surgeons during cancer removal. The goal of these drugs and devices is to clearly distinguish cancer from normal tissue to improve surgical outcome for cancer patients.