Microcycles are head-to-tail cyclic hexapeptides that hold much promise for drug discovery against the most challenging targets. Here, we will detail several platforms for the preparation of genetically encoded Microcycle libraries in cells and in microfluidic droplets. These libraries have been interfaced with a number of high-throughput assays for the direct identification of functional inhibitors of various transcription factors, protein-protein and protein-DNA interactions, including several first in class compounds. The presentation will include examples in which Microcycle hits from these screens have been scaffold-hopped into small moleculesas a first step towards clinical candidates.