While current trials of anticancer agents serve to provide a population-based validation of therapeutic activity, clinical success is typically restricted to tumors of select molecular subtype. Recent insights have yielded a growing catalogue of germline and tumor-based aberrations that can predetermine whether a patient will achieve clinical benefit from a drug or not. Thus, in order to realize the true potential of anticancer agents, we need to define the molecular contexts under which they will prove both efficacious and safe. In this article, we provide an overview of such molecular determinants and introduce the concept of 'cancer patient profiling' - the process and science of defining the optimal therapy for a given patient through the generation and analysis of system-wide molecular information.