Abstract 3D organoids are emerging as a powerful tool for stem cell biology and tissue modeling, but their broader adoption for screening applications has been hindered by their slow expansion and heterogeneity. To overcome these two limitations, we request the Dolomite Nadia Innovate, a microfluidic droplet protocol development instrument that will enable us to invent two novel organoid screening platforms: (1) Droplet Miniature Organoid Spheres (DMOS) that can expand quickly, preserve tissue heterogeneity, and support high-throughput screen, and (2) a CRISPRi Organoid Screening by Multiplexed IndeXing (COSMIX) platform to identify stem cell and tissue plasticity regulators. If successful, our invention of droplet-based high-throughput organoid functional assays will be transformative in a way similar to droplet-based single-cell sequencing, which has changed our understanding of tissue heterogeneity.