Recent advancements in stem cell-derived islet products have shown promising potential for cell replacement therapies in treating type 1 diabetes. However, controlling endocrine differentiation, particularly in relation to alpha and delta cells, remains a challenge. In this talk, we will discuss our work in developing protocols for the directed differentiation of human pancreatic alpha and delta cells from pluripotent cell sources through the use of drug screening approaches. The resulting cell populations have demonstrated the ability to mimic many aspects of alpha and delta cell biology, offering a unique human source of these endocrine cell types. These stepwise protocols have also effectively replicated many aspects of pancreatic developmental biology, while also highlighting novel differentiation programs leading to the development of endocrine cell types. Proper production and paracrine signaling between these endocrine cells are critical for the optimal function of engineered islet products and will be instrumental in the future of cell replacement therapies. Ultimately, we hope to provide insights into the innovative techniques used to control endocrine differentiation and the potential applications of these protocols for developing more effective islet replacement therapies for diabetes patients.