Non-genetic adaptive mechanisms of acquired targeted therapy resistance have emerged as a barrier to curative treatment in melanoma. Recent insights from the clinic and experimental settings have highlighted a range of non-genetic adaptive mechanisms that contribute to therapy resistance and disease relapse, including transcriptional, post-transcriptional and metabolic reprogramming. A growing body of evidence highlights the inherent plasticity of melanoma metabolism, evidenced by reversible metabolome alterations and flexibility in fuel usage that occur during metastasis and response to anti-cancer therapies. Indeed, early during adaptive resistance, a starved-like melanoma cell (SMC) state emerges that is characterized by altered expression of multiple nutrient transporters. However, what nutrients fuel drug tolerant melanoma cells that persist following treatment and give rise to resistance is poorly understood. Here, we will determine the nutrient dependencies of drug tolerant melanoma cells following exposure to MAPK pathway targeted therapies using a physiologically defined growth media, Plasmax. Plasmax replicates the composition of human plasma and is a powerful system for determining specific nutrient dependencies. Our preliminary data indicates that Plasmax is a suitable model for assessing therapy response in BRAF mutant melanoma cells as it does not significantly alter proliferation rate, cellular morphology or sensitivity to MAPK pathway targeted therapies when compared to standard growth media (RPMI). Moreover, expression of SMC biomarkers, initially identified in patient derived mouse models and patient samples following treatment with MAPK pathway targeted therapies, are also observed in our cell culture systems. Thus, our preliminary data establishes that Plasmax is a suitable model that can be used to dissect the specific nutrient requirements of drug tolerant SMC populations. Targeting metabolic features of drug tolerant cells that persist following treatment with anti-cancer therapies represents a therapeutic opportunity to overcome acquired resistance and tumour relapse, thus further characterization of SMC populations may prove useful therapeutically.