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Clinical utility of targeted RNA sequencing in cancer molecular diagnostics. Molecular diagnostics in oncology uses next-generation sequencing to improve diagnostic precision, prognostic prediction and therapeutic target selection. To date, most approaches have focused on DNA-based sequencing. However, RNA sequencing (RNA-seq) enables superior fusion detection and functional characterization of other alterations including splice site mutations and expression changes. Here we report our prospective, real-world, clinical experience using a single, targeted RNA-seq assay on 2,310 solid, central nervous system and hematopoietic neoplasms from children and adults (range 0-90 years). RNA-seq performed as well as DNA-based diagnostics, with a 4.8% failure rate despite the fact that most samples were formalin fixed and paraffin embedded, and provided valuable molecular data for 87% of patients, including diagnostic alterations that resulted in revised diagnoses and the identification of clinically actionable alterations that led to a change in treatment for patients, including the administration of targeted therapies. Our experience supports the use of RNA-seq as a stand-alone tool for precision clinical diagnostics, minimizing cost, tissue requirement and turnaround time.