In the 2 decades since the US Food and Drug Administration (FDA) approval of imatinib for treatment of chronic myeloid leukemia, the paradigm of biomarker-guided therapeutics has produced major clinical breakthroughs for subsets of patients with cancer. This remarkable progress has been largely fueled by development of therapeutics against what we term first-order targets, or molecular signaling nodes that drive a cellular pathway essential for cancer survival and proliferation. These are typically kinases abnormally activated via gain-of-function genetic alterations present in founding tumor cells, leading to their universal presence within a cancer population. While cellular plasticity or compound genetic alterations can still abrogate therapeutic efficacy, monotherapy inhibition of a first-order target can lead to frequent and profound clinical responses. Notable examples include the clinical success of anaplastic lymphoma kinase inhibitors against anaplastic lymphoma kinase fusion–positive non–small cell lung cancer.