Recent progress in discerning the molecular events that accompany carcinogenesis has led to development of new cancer therapies directly targeted against the molecular changes of neoplasia. Molecular-targeted therapeutics have shown significant improvements in response rates and decreased toxicity as compared to conventional cytotoxic therapies which lack specificity for tumor cells. In order to fully explore the potential of molecular-targeted therapy, a new set of tools is required to dynamically and quantitatively image and monitor the heterogeneous molecular profiles of tumors in vivo. Currently, molecular markers can only be visualized in vitro using complex immunohistochemical staining protocols. In this chapter, we discuss emerging optical tools to image in vivo a molecular profile of risk-based hallmarks of cancer for selecting and monitoring therapy. We present the combination of optically active, targeted nanoparticles for molecular imaging with advances in minimally invasive optical imaging systems, which can be used to dynamically image both a molecular and phenotypic profile of risk and to monitor changes in this profile during therapy.