Despite significant scientific advances over the last decade in the field of chemotherapeutics and cellular targets, there still remains the need for improved therapeutic modalities. Photodynamic therapy (PDT), a minimally invasive therapeutic modality, has been shown to be effective in a number of oncologic and non-oncologic conditions. However, in the skin cancer milieu, a number of factors contribute to therapeutic resistance. Two important considerations include the tumor microenvironment (TME) and the expression and/or upregulation of ATP-binding cassette (ABC) transporters. The TME is hypoxic and has a low pH. Furthermore, it comprises the extracellular matrix (ECM) proteins (e.g. Matrix metalloproteinases and collagens), adhesion molecules (eg. integrins and cadherins), cancer-associated fibroblasts, endothelial cells, cytokines and immune cells (neutrophils and macrophages). PDT has been shown to affect ECM proteins such as MMPs and collagen as well as the expression of certain adhesion molecules such as intracellular adhesion molecule 1 (ICAM-1) and vascular adhesion molecule 1 (VCAM-1). Furthermore, PDT seems to increase cytokine secretion of IL 6 and tumor necrosis factor α (TNF-α) and vascular endothelial growth factor, thereby directly stimulating the immune response and the vascular system. In addition, we and others have recently reported on the efficacy of PDT in combating melanoma due to photosensitizer co-localisation within melanosomes. This data was in contrast to reports where the overexpression of transporters ABCC1 and ABCG2 in adenocarcinoma cancer reduced the hypericin-mediated PDT killing efficiency. PDT resistance has also been recently linked to a small subpopulation of cancer-associated stem-like cells which survive through autophagic induction. This review will explore the effect of PDT on both the TME and the family of ATP transporters and attempt to elucidate mechanisms which potentially will enhance the destruction of these recalcitrant tumors.