Current cancer therapies target a limited set of tumor features, rather than considering the tumor as a whole. Systems biology aims to reveal therapeutic targets associated with a variety of facets in an individual's tumor, such as genetic heterogeneity and its evolution, cancer cell-autonomous phenotypes, and microenvironmental signaling. These disparate characteristics can be reconciled using mathematical modeling that incorporates concepts from ecology and evolution. This provides an opportunity to predict tumor growth and response to therapy, to tailor patient-specific approaches in real time or even prospectively. Importantly, as data regarding patient tumors is often available from only limited time points during treatment, systems-based approaches can address this limitation by interpolating longitudinal events within a principled framework. This review outlines areas in medicine that could benefit from systems biology approaches to deconvolve the complexity of cancer.