Pancreatic islet development can be viewed through the lens of Waddington’s epigenetic landscape, where cells traverse branching trajectories and commit to endocrine identities at key developmental bifurcations. In this project, we aim to synthetically redesign that landscape by manipulating non-coding DNA elements—such as promoters and enhancers—that orchestrate gene expression during pancreas development. We apply these strategies to improve stem cell-derived β-cell (SC-β-cell) differentiation, with the ultimate goal of producing more consistent, functional, and therapeutically relevant cells for type 1 diabetes (T1D) cell replacement therapy. This work integrates computational modeling, genome engineering, and single-cell and functional genomics to reprogram stem cell developmental trajectories.