Clinical next generation sequencing (NGS) is a term that refers to a variety of technologies that permit rapid sequencing of large numbers of DNA segments, up to and including entire genomes. As an approach that is playing an increasingly important role in obtaining genetic information from patients, it may be viewed by public and private payers either positively, as an enabler of the promised benefits of personalized medicine, or as “the perfect storm” resulting from the confluence of high market demand, an uproven technology, and an unprepared delivery system. A number of recent studies have noted that coverage and reimbursement will be critical for clinical integration of NGS, yet the evidentiary pathway for payer decision-making is unclear. Although there are multiple reasons for this uncertain reimbursement environment, the situation stems in large part from a long-standing lack of alignment between the information needs of regulators and post-regulatory decision-makers such as payers.