Next-generation sequencing (NGS)-based technology has lowered the cost of cancer testing for genomic alterations and is now commercially available from a growing number of diagnostic laboratories. However, laboratories vary in the methodologies underlying their tests, the types and numbers of genomic alterations covered by the test, and the clinical annotation of the sequencing findings. Determining the value of NGS tests is dependent on whether it is used to support clinical trials or as a part of routine clinical care at a time when both the investigational drug pipeline and the list of U.S. Food and Drug Administration-approved or Compendium-listed therapeutics is in a high state of flux. Reimbursement policy for NGS testing by the Centers for Medicare & Medicaid is evolving as the value of NGS testing becomes more clearly defined for specific clinical situations. Patient care and clinical decisions-making are dependent on the oncologist's knowledge of when NGS testing has value. Here, we review principles and practice for NGS testing in this dynamic confluence of technology, cancer biology, and health care policy.