International efforts to sequence the genomes of various human cancers have been broadly deployed in drug discovery programmes. Diagnostic tests that predict the value of the molecularly targeted anticancer agents used in such programmes are conceived and validated in parallel with new small-molecule treatments and immunotherapies. This approach has been aided by better preclinical cancer models; an enhanced appreciation of the complex interactions that exist between tumour cells and their microenvironment; the elucidation of interactions between many of the genetic drivers of cancer, including oncogenes and tumour suppressors; and recent insights into the genetic heterogeneity of human tumours made possible by extraordinary improvements in DNA-sequencing techniques. These advances are being employed in the first generation of genomic clinical trials that will examine the feasibility of matching a broad range of systemic therapies to specific molecular tumour characteristics. More-extensive molecular characterization of tumours and their supporting matrices are anticipated to become standard aspects of oncological practice, permitting continuous molecular re-evaluations of human malignancies on a patient-by-patient and treatment-by-treatment basis. We review selected developments in translational cancer biology, diagnostics, and therapeutics that have occurred over the past decade and offer our thoughts on future prospects for the next few years.