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The advent of next-generation sequencing has accelerated the implementation of genomic profiling in the care and management of patients with cancer. Initial efforts have focused on target identification in patients with advanced cancer. Prognostication, resistance detection, disease monitoring, and early detection efforts are also underway. This review highlights some of the challenges in this evolving space. This includes choosing between gene-panel and comprehensive approaches, DNA and transcriptome data integration, reduction of false-positive variants, addressing tumor heterogeneity, establishment of workflows to address unsolicited findings, and data sharing and privacy concerns.