Recent studies have shown that intratumor heterogeneity contributes to drug resistance in advanced disease. Intratumor heterogeneity may foster the selection of a resistant subclone, sometimes detectable prior to treatment. Next-generation sequencing is enabling the phylogenetic reconstruction of a cancer’s life history and has revealed different modes of cancer evolution. These studies have shown that cancer evolution is not always stochastic and has certain constraints. Consideration of cancer evolution may enable the better design of clinical trials and cancer therapeutics. In this review, we summarize the different modes of cancer evolution and how this might impact clinical outcomes. Furthermore, we will discuss several therapeutic strategies for managing emergent intratumor heterogeneity.