It is estimated that between 80 and 90% of mortality in cancer patients is directly or indirectly related to drug resistance. Consequently, overcoming drug resistance represents a significant challenge in the treatment of cancer. Integrins are transmembrane adhesion molecules that facilitate the linkage between the extracellular matrix (ECM) and the cytoskeleton, thereby enabling the activation of various cellular signaling pathways. Integrins are highly expressed in various cancers and contribute to cancer progression through invasion and metastasis. In addition, recent studies have revealed that integrins play a pivotal role in the development of drug resistance in cancer. This review will first provide an overview of integrin function and classification. It then discusses recent advances in understanding how integrins contribute to drug resistance in cancer, with a focus on ECM, drug transporters, the epithelial-to-mesenchymal transition (EMT), cancer stemness, PD-L1, and glycosylation. Finally, the potential applications of integrins as targets for therapeutic agents against drug-resistant cancers are also summarized.