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Photodynamic therapy (PDT) is a promising non-invasive therapy approach for various diseases including malignant tumor. The process of PDT involves three interrelated aspects, namely photosensitizer (PS), light source, and oxygen, among which PS is the decisive factor that determines its anticancer efficiency. There exist some defects in currently applied PDT, such as inadequate production of reactive oxygen species (ROS), poor penetration of exciting light, insufficient oxygen supply, and nonselective distribution of PS. With unique physicochemical and optical properties, two-dimensional nanomaterials (2DNMs) have aroused great interest in biomedical fields. 2DNMs-based PDT is promising to significantly improve antitumor efficacy compared to conventional PDT. In this review, we will firstly introduce the underlying mechanism of PDT and how 2DNMs are absorbed and distribute inside tumor cells. After that, we will not only illustrate how 2DNMs-based PDT can enhance tumor-killing efficacy and minimize side-effects through conquering the above-mentioned defects of conventional PDT and the preparation process of 2DNMs, but also elaborate recent advances about 2DNMs-based PDT. Lastly, we will summarize the challenges and future prospects of 2DNMs-based PDT.