In 2013 Actelion decided to establish a Compound Library Committee (CLC), a cross-functional team consisting of computational scientists, medicinal chemists, and biologists. The CLC was endowed with a significant annual budget for new screening compound purchases. Based on an initial library analysis performed in 2013, the CLC developed a New Library Strategy. The structural library quality was increased which was achieved by shifting the selection criteria from ‘druglike’ to ‘leadlike’ structures, enriching for non-flat structures, aiming for compound novelty, and increasing the ratio of higher cost ‘Premium Compounds’. Novel chemical space was gained by adding natural products, macrocycles, designed and focused libraries to the collection, and through mutual exchanges of proprietary compounds with agrochemical companies. A comparative analysis in 2016 provided evidence for the positive impact of all these measures on new lead discovery. Screening the improved library has provided several highly promising hits that are currently followed up in different Hit-to-Lead and Lead Optimization programs, including a compound in pre-clinical development. The goal of the CLC was not to achieve higher HTS hit rates, but to increase the chances of identified hits to serve as the basis for successful early drug discovery programs. Today, eight years later, lessons learned from successes and flaws will help the CLC shape the future Idorsia Library Strategy.