Melanoma, the most lethal form of skin cancer, presents significant treatment challenges because of its early metastasis and dormancy. Despite substantial advancements in melanoma research, particularly in understanding molecular alterations during early tumor development and melanoma progression, a comprehensive understanding remains elusive. In tumor therapy, novel therapeutic modalities, such as targeted therapies such as inhibition of mutated BRAF, have been introduced. However, primary and secondary therapy resistance continue to present major challenges. Testing of new therapeutic options in 2D cell culture is limited because drugs can work convincingly in 2D experiments while resistance can occur in vivo . In our study, we aimed to overcome the limitations of 2D cell culture using a 3D biomaterial model, in which we embedded melanoma cells and melanoma cell spheroids in alginate to analyze the therapeutic effects in a 3D structure. We treated the embedded cells or spheroids with different concentrations of either sorafenib or vemurafenib to investigate drug response. We chose these compounds because vemurafenib is an FDA-approved drug that is widely used to treat melanoma harboring the BRAF V600E mutation, and sorafenib was tested in preclinical trials in melanoma but failed in clinical trials. We showed that our 3D model was able to reproduce the findings of the in vivo studies, as we observed resistance to the drug in response to sorafenib treatment after 4 weeks. Taken together, the results of this study highlight the potential of user-friendly alginate 3D cell culture models for several aspects of melanoma drug development.