Here we build upon our previous reports to develop a protocol for the generation of SC-alpha cells. The protocol robustly produces a transient pre-alpha cell intermediate, which has a transcriptional signature similar to alpha cells except that they express insulin in addition to glucagon. We identify a small molecule capable of driving pre-alpha cells to an alpha cell identity and demonstrate the ability to produce approximately 30% SC-alpha cells in vitro. Our results show that these SC-alpha cells have a transcriptional signature similar to human cadaveric alpha cells, are responsive to some glucagon secretagogues, and elicit a robust physiological response within 4 weeks of transplantation in mice. The SC-alpha cells generated can recapitulate central aspects of alpha cell biology and represent an efficient and scalable avenue to produce alpha cells for use in islet organoids for cell replacement therapy, drug screening, disease modeling, and may accelerate exploration of alpha cell biology.