Despite the increased use of molecular diagnostics, the extent to which patients who have these tests harbor potentially actionable aberrations is unclear. We retrospectively reviewed 439 patients with diverse cancers, for whom next-generation sequencing (mostly 236-gene panel) had been performed. Data pertaining to the molecular alterations identified, as well as associated treatment suggestions (on- or off-label, or experimental), were extracted from molecular diagnostic reports. Most patients (420/439; 96%) had at least one molecular alteration: 1,813 alterations (in 207 distinct genes) were identified [the majority being mutations (62%) or amplifications (29%)]. The three most common gene abnormalities were TP53 (44%), KRAS (16%), and PIK3CA (12%). The median number of alterations per patient was 3 (range, 0–16). Nineteen patients (4%) had no alterations; 48 patients (11%) had only one alteration; and 372 patients had two or more abnormalities (85%). The median number of potentially actionable anomalies per patient was 2 (range, 0–8). Most patients (393/439; 90%) had at least one potentially actionable alteration, and in all these cases the aberration could at least be targeted by an experimental drug in a clinical trial. A total of 307 patients (70%) had an alteration that was actionable with an approved drug, but in only 89 patients (20%) was the drug approved for their disease (on-label). Next-generation sequencing identified theoretically actionable aberrations in 90% of our patients. Many of the drugs are, however, experimental or would require off-label use. Strategies to address drug access for patients harboring potentially actionable mutations are needed. Mol Cancer Ther; 14(6); 1488–94. ©2015 AACR.