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Photodynamic therapy (PDT) of cancer is a two-step drug-device combination modality, which involves the topical or systemic administration of a photosensitizer followed by light illumination of cancer site. In the presence of oxygen molecules, the light illumination of photosensitizer (PS) can lead to the generation of cytotoxic reactive oxygen species (ROS) and consequently destroy cancer. Similar to many other anticancer therapies, PDT is also subject to intrinsic cancer resistance mediated by multidrug resistance (MDR) mechanisms. This paper will review the recent progress in understanding the interaction between MDR transporters and PS uptake. The strategies that can be used in a clinical setting to overcome or bypass MDR will also be discussed.