Cancer is a major public health problem. In the last decade, enormous progress has been made to understand the molecular events that accompany carcinogenesis. The identification of unique molecular markers of cancer and the associated processes they modulate has led to the development of new molecular cancer therapies that affect these processes. There is an important need to image the molecular features of cancer in vivo. Progress toward a molecular characterization of cancer would have important clinical benefits, including (1) detecting cancer earlier, (2) predicting the risk of precancerous lesion progression, (3) detecting margins in the operating room in real time, (4) selecting molecular therapy rationally and (5) monitoring response to therapy in real time at a molecular level. Coupled advances in nanobiotechnology, MEMS and imaging science are required to achieve these important goals. A comprehensive strategy is needed to develop inexpensive, rugged and portable optical imaging systems for molecular imaging of cancer, which couples the development of nanoparticle-based, optically active contrast agents with advances in functional genomics of cancer. Work is ongoing to develop optically active contrast agents than can be applied topically to areas of tissue at risk, to monitor the three-dimensional profile of the targeted biomarkers as well as morphologic and architectural biomarkers such as nuclear to cytoplasmic ratio. It is believed these contrast agents and imaging systems will have broad applicability to detect and monitor many types of cancer. At the same time, optical systems to image the morphologic and molecular signatures of neoplasia noninvasively are being developed. These real-time, portable, inexpensive systems can provide tools to characterize the molecular features of cancer in vivo.