Macrocycles offer a new structural class that has the potential to address challenging protein-protein interaction targets and still present attractive drug-like properties including cell membrane penetration and oral bioavailability. Indeed a number of orally active drugs based on naturally occurring macrocycles provide a compelling precedent for this argument. Ensemble have used DNA-programmed chemistry to make over 10 million synthetic macrocycles in a library format that permits rapid and efficient screening against therapeutically relevant targets. The talk will present successful Ensemble case studies with XIAP antagonists for oncology, and IL17 antagonists for inflammatory disease.