The integration of next-generation sequencing (NGS) tests into clinical laboratory practice across medical disciplines provides medically actionable data that in some cases are not otherwise attainable. This presentation will describe evolving guidance and private/public funded initiatives developed to promote the effective and safe use of NGS for patient care. Integration of NGS into clinical laboratory practice created novel challenges and approaches for test validation, quality assurance, result interpretation, reporting, and compliance with regulatory requirements. Data analysis, storage, and medical coding presents other challenges that require significant informatics expertise not traditionally a component of laboratory practice. The capability to sequence the human genome, pathogens, and the human microbiome provides the opportunity to collect data having immediate and potentially future clinical relevance, blurring the line between medical and research applications. In some instances, the laboratory assumes an enhanced consultative role to advise clinicians about test selection, variant interpretation, and the limitations of NGS; knowledge required to inform clinical decision-making. This professional consultative role is essential toward assuring appropriate test utilization and as a resource for clinicians who are less familiar with NGS and do not have the time to establish and maintain expertise in this rapidly evolving area of laboratory medicine.