Understanding the distinct molecular features of solid tumors provides the opportunity to develop more targeted and effective therapies. The evaluation and monitoring of these therapies require sophisticated laboratory and imaging technologies to detect potential benefit not necessarily translating into significant changes in tumor size. PET has emerged as the most sensitive imaging technique for providing the metabolic profile of an individual tumor. Most recently, the detection of circulating tumor cells in the peripheral blood of patients with advanced malignancies has provided another dimension to the use of PET for sensitive therapeutic monitoring. Moreover, molecular characterization of circulating tumor cells holds promise for furthering the care of cancer patients.