The role of tumor–stromal interactions in progression is generally well accepted, but their role in initiation or treatment is less well understood. It is now generally agreed that, rather than consisting solely of malignant cells, tumors consist of a complex dynamic mixture of cancer cells, host fibroblasts, endothelial cells and immune cells that interact with each other and microenvironmental factors to drive tumor progression. We are particularly interested in stromal cells (for example fibroblasts) and stromal factors (for example fibronectin) as important players in tumor progression since they have also been implicated in drug resistance. Here we develop an integrated approach to understand the role of such stromal cells and factors in the growth and maintenance of tumors as well as their potential impact on treatment resistance, specifically in application to melanoma. Using a suite of experimental assays we show that melanoma cells can stimulate the recruitment of fibroblasts and activate them, resulting in melanoma cell growth by providing both structural (extracellular matrix proteins) and chemical support (growth factors). Motivated by these experimental results we construct a compartment model and use it to investigate the roles of both stromal activation and tumor aggressiveness in melanoma growth and progression. We utilize this model to investigate the role fibroblasts might play in melanoma treatment resistance and the clinically observed flare phenomenon that is seen when a patient, who appears resistant to a targeted drug, is removed from that treatment. Our model makes the unexpected prediction that targeted therapies may actually hasten tumor progression once resistance has occurred. If confirmed experimentally, this provocative prediction may bring important new insights into how drug resistance could be managed clinically.