Melanoma is a type of skin cancer originating from melanocytes within the epidermis and is responsible for approximately 75% of all skin cancer related deaths. While there are promising new treatments, melanoma remains notoriously drug resistant. The goal of this research is to develop and test a hydrogel system as a clinically relevant in vitro model to understand how the microenvironment contributes to drug resistant behavior and then utilize this system as a drug screening model. Here, we explore a 3D culturing platform based on fully synthetic thiolene PEG hydrogels with the goal of capturing critical aspects of in vivo-like tumor microenvironments. We aim to develop a bridge between traditional 2D culture and in vivo animal experiments by developing a robust 3D in vitro culture system to better recapitulate drug resistant behavior of melanoma. Initially, our research focuses on BRAF and MEK inhibitors, which are currently being pursued as potent inhibitors of cancer growth, viability, and migration. Using this model, our current research focuses on characterizing the drug-induced effects on cells seeded on top thiolene matrices and the role of the matrix environment in promoting or suppressing these cytotoxic effects.