Understanding the molecular landscape of cancer has facilitated the development of diagnostic, prognostic, and predictive biomarkers for clinical oncology. Developments in next generation DNA sequencing technologies have increased the speed and reduced the cost of sequencing the nucleic acids of cancer cells. This has unlocked opportunities to characterize the genomic and transcriptomic landscapes of cancer for basic science research through projects such as The Cancer Genome Atlas. The cancer genome includes DNA-based alterations such as point mutations or gene duplications. The cancer transcriptome involves RNA-based alterations including changes in messenger RNAs. Together the genome and transcriptome can provide a comprehensive view of an individual patient’s cancer and is beginning to impact real-time clinical decision-making. We discuss several opportunities for translating this basic science knowledge into clinical practice including a molecular classification of cancer, heritable risk of cancer, eligibility for targeted therapies, and the development of innovative genomic-based clinical trials. In this review, we outline key applications and new directions for translating the cancer genome and transcriptome into patient care in the clinic.