Comprehensive genomic profiling is rapidly becoming the standard of care for the management of solid tumors. These assays leverage modern next-generation sequencing technologies to characterize the molecular attributes of solid tumors. Molecular results are increasingly required for accurate diagnosis and prognosis and for selecting appropriate personalized therapy. Today’s commonly used assays can report a variety of molecular findings. Through DNA sequencing, single-nucleotide variants and small insertions and deletions in oncogenes and tumor suppressor genes are identified. Through copy number analysis, amplifications and deletions can be reported. Many assays also incorporate an RNA sequencing component for the identification of oncogenic fusions and splice variant transcripts. Finally, global evaluation of molecular phenotype allows for the identification of the recently emerged molecular biomarkers including tumor mutational burden, microsatellite instability, and homologous recombination repair deficiency. This chapter describes these molecular findings in the context of tumor biology, describes how they are identified through modern comprehensive genomic profiling, and highlights benefits and drawbacks of next-generation sequencing compared to traditional molecular techniques.