Most patients with advanced cancer die because their cancer exhibits or develops resistance to available therapies. This challenge remains pervasive despite many remarkable advances in cancer biology and treatment and has motivated renewed efforts to understand and combat cancer drug resistance. For example, addressing cancer drug resistance was one of the key recommendations from the Blue Ribbon Panel that advised the Beau Biden Cancer Moonshot initiative (Jacks et al., 2016). Studies of cancer drug resistance yield several types of insights. First, defining mechanisms of resistance to a specific anti-cancer regimen may identify future therapeutic strategies against such resistance. Such knowledge might guide salvage treatment after resistance has already occurred or inform new up-front strategies that prevent its emergence. For example, identification of MEK reactivation as a mechanism of resistance to RAF inhibitor monotherapy in BRAF-mutant melanoma (Johannessen et al., 2010; Nazarian et al., 2010), or of EGFRT790M as a mechanism of resistance to first-generation EGFR inhibitors in EGFR-mutant lung cancer (Kobayashi et al., 2005; Pao et al., 2005), led to the development of new therapies with clinical efficacy against these resistance mechanisms (Mok et al., 2017; Robert et al., 2015). Systematic characterization of drug resistance across tumor types and therapeutic categories may also enable new insights into cancer biology—regarding, for example, networks that differentiate the malignant state from normal, the cell-intrinsic and extrinsic factors regulating them, and how these pathways evolve to promote tumor survival during therapy. Investigating resistance to mitogen-activated protein kinase (MAPK) pathway inhibition revealed new aspects of feedback regulation within this pathway (Lito et al., 2014; Pratilas et al., 2009). Likewise, studies of EGFR inhibitor resistance in lung cancer highlighted the importance of intratumoral heterogeneity (Piotrowska et al., 2015). Despite the potential benefits of such knowledge, systematic efforts to define the full spectrum of resistance mechanisms for any given therapeutic remain the exception rather than the rule in cancer research. In fact, the skeptic might even question whether studies of resistance in general offer the most efficient or incisive means to discover either novel therapeutic targets or disease-relevant biology. However, a synthesis of emerging genomic and functional portraits of cancer drug resistance begins to reveal overarching frameworks that both offer new insights into resistant states and suggest possible therapeutic approaches to overcome them.