The advent of next-generation sequencing, and its transition further into the clinic with the US Food and Drug Administration approval of a cystic fibrosis assay in 2013, have increased the speed and reduced the cost of DNA sequencing. Coupled with a historic ruling by the Supreme Court of the United States that human genes are not patentable, these events have caused a seismic shift in genetic testing in clinical medicine. More labs are offering genetic testing services; more multigene panels are available for gene testing; more genes and gene mutations are being identified; and more variants of uncertain significance, which may or may not be clinically actionable, have been found. All these factors, taken together, are increasing the complexity of clinical management. While these developments have led to a greater interest in genetic testing, risk assessment, and large-scale population screening, they also present unique challenges. The dilemma for clinicians is how best to understand and manage this rapidly growing body of information to improve patient care. With millions of genetic variants of potential clinical significance and thousands of genes associated with rare but well-established genetic conditions, the complexities of genetic data management clearly will require improved computerized clinical decision support tools, as opposed to continued reliance on traditional rote, memory-based medicine.