The concept of precision cancer medicine, including systematic molecular characterization of tumor samples for use in care decisions, is undergoing prospective evaluation in populations of patients with advanced cancer. Such studies have already enabled numerous significant discoveries in translational cancer research. Although much of the emphasis in these programs has centered around somatic analysis of tumor samples for therapeutic predictive utility, molecular tests that sequence both tumor tissue for somatic alterations (an alteration in DNA that occurs after conception) and normal tissue for germline alterations (a mutation in the lineage of germ cells that are transmitted to offspring) may yield even more detailed characterization of molecular events for diagnostic, prognostic, and predictive purposes. For specific clinical contexts, retrospective germline analysis of patients with cancer has resulted in an expanded understanding of inherited cancer predisposition. Recent examples that highlight new germline genetic discoveries with immediate clinical application for inherited risk assessment involve cancer predisposition genes in pediatric cancers and DNA repair genes in advanced prostate cancer. In each study, the availability of large-scale molecular data obtained in focused clinical settings has enabled effective dissection of germline pathogenic variation, and these discoveries may change clinical practice and improve patient outcomes.