Abstract In June 2017, SEngine Precision Medicine (Seattle, WA USA) obtained CLIA certification for the first high-complexity and high throughput organotypic chemosensitivity test, P.A.R.I.S., thus opening its doors to oncologists and pharmaceutical companies that may consider personalization of cancer treatments in their practice or in the clinical trial setting. Just as Paris slayed the invulnerable Achilles by aiming specifically at its weaknesses, the PARIS test challenges tumor cells with a library of 137 clinically actionable targeted drugs to identify sensitivity and resistance patterns unique to each individual cancer in an unbiased manner. Here we will present an overview of the approach that has led to CLIA certification, including novel cell culture techniques and analysis metrics. We will also highlight insights gained by comparative analysis across a multitude of cancer samples. SEngine has derived and expanded primary cancer cells from a cohort of over 100 patient derived specimens. Patients include many who have been heavily pre-treated with prior chemotherapy and several with rare cancers, including adrenocortical carcinoma, neuroblastoma, leiomyosarcoma and cholangiocarcinoma. Standard operating procedures have been established for transport of specimens as well as primary cultures in three dimensional organotypic conditions. Our analysis pipeline evaluates the multi-dose response of a given patient's tumor to each drug in our library and compares those responses to all prior patients. This establishes not only functional sensitivity but also the uniqueness of the patient's response. We calculate the SPM score, a proprietary ranking metric weighing both the sensitivity and uniqueness of the response. The results from the P.A.R.I.S. test are highly reproducible (Spearman rank correlation coefficients: 0.95, 0.88 technical and biological replicates respectively). We perform bi-annual proficiency validation of our platform with another CLIA-certified laboratory. Ten samples tested demonstrated greater than 75% concordance between responses. The data obtained are visualized by an in-house application suite (SEngine Medicine APP), consisting of interactive charts, statistical analysis, and reactive reports which can be shared with oncologists and investigators. A cohort of 50 samples was employed to demonstrate sensitivities or resistances concordant with those predicted by the patient's genomic aberrations and/or prior clinical responses.In summary, we envision that the P.A.R.I.S. test will be essential for patient's selection while developing novel targeted drugs, providing crucial functional information much needed to decode the complexity of individual cancer genomics. Citation Format: Hallie A. Swan, Michael J. Churchill, Rachele Rosati, Franz X. Schaub, Reid C. Shaw, Roland M. Watt, Eduardo Mendez, Christopher J. Kemp, Vijayakrishna K. Gadi, Stephanie A. Murphy, Brady Bernard, Robert L. Diaz, Shalini C. Pereira, Carla Grandori. Personalization of cancer treatments with a CLIA-certified high-complexity and high-throughput drug sensitivity test [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1605.