Background: Certain tumor types show dramatic responses to targeted treatments based on demonstration of the corresponding molecular abnormality. The NCI-MATCH study hypothesizes that patients (pts) across a range of histologies whose tumors share molecular abnormalities that have been shown to respond to a targeted treatment may respond to that same treatment, and that responsiveness or resistance may be predictable by concurrent molecular abnormalities. Methods: Pts with refractory solid tumors or lymphomas have molecular profiling on a proximate biopsy, using a validated, locked next generation sequencing (NGS) assay (143 genes; single nucleotide variants, copy number variants and fusions) and selected other molecular assays. The trial will have > 20 phase II targeted treatments (arms). Drugs are provided by various pharmaceutical companies and could be FDA approved or investigational single agents or combinations. The arms are placed under a “master protocol”, allowing new arms to be added to replace a filled cohort or to add a new molecularly based treatment. Specific rules are established to qualify the selection of the molecular subtype and to select the candidate treatment. A rules engine assigns pts to molecularly targeted treatments based on actionable mutation of interest (aMOI), as well as other factors that inform about likelihood of response. Each arm will enroll 35 pts (one stage design) with appropriate aMOI, regardless of histopathologic tumor type. The primary endpoint is response rate (5% vs 25%). Biopsy is requested upon progression. This trial opened in August 2015. Currently 798 of a planned 3000 patients have been screened. A protocol-directed pause in accrual occurred after 3 months, and interim analysis (feasibility) is ongoing. The current 10 arms and additional arms in the process of being added address molecular abnormalities in: EGFR, ERBB2, PIK3CA, PTEN, ALK, ROS, BRAF, NRAS, NF2, KIT, NF1, SMO, PTCH1, MET, FGFR, AKT, NTRK, cell cycle and PI3K pathway as well as other less common molecular abnormalities. Data from the NCI-MATCH trial is designed to identify signals from molecularly targeted treatment that will inform and accelerate further therapy development leading to clinical benefit. Clinical trial information: NCT02465060