Advances in tumor genome sequencing have enabled discovery of actionable alterations leading to novel therapies. Currently, there are approved targeted therapies across various tumors that can be matched to genomic alterations, such as point mutations, gene amplification, and translocations. Tools to detect these genomic alterations have emerged as a result of decreasing costs and improved throughput enabled by next-generation sequencing (NGS) technologies. NGS has been successfully utilized for developing biomarkers to assess susceptibility, diagnosis, prognosis, and treatment of cancers. However, clinical application presents some potential challenges in terms of tumor specimen acquisition, analysis, privacy, interpretation, and drug development in rare cancer subsets. Although whole-genome sequencing offers the most complete strategy for tumor analysis, its present utility in clinical care is limited. Consequently, targeted gene capture panels are more commonly employed by academic institutions and commercial vendors for clinical grade cancer genomic testing to assess molecular eligibility for matching therapies, whereas whole-exome and transcriptome (RNASeq) sequencing are being utilized for discovery research. This review discusses the strategies, clinical challenges, and opportunities associated with the application of cancer genomic testing for precision cancer medicine.