Colorectal cancer is one of the most frequent cancers with a high burden on society. Hundreds of thousands of people are diagnosed each year with colorectal cancer. Despite available treatments, the survival of patients with advanced-stage colorectal cancer is poor. Stemness of neoplastic cells has been proposed as a major factor in treatment resistance and high relapse rates, however, drugs targeting stem cell signaling pathways in cancer are still lacking today. The EU-funded ACHILLEUS project aims to develop and validate a novel drug discovery platform that involves patient-derived organoids (PDOs) and phenotypic machine learning-assisted validation to identify therapeutics to target colorectal cancer stem cell signaling pathways. Researchers will target colorectal cancer stem cell signaling pathways to shift the balance between stem cells and differentiated cells, using the targeting of the Wnt pathway as a proof of principle. The goal is to create a new company based on a phenotypic drug discovery platform for targeting cancer stem cell signaling.