Abstract <p>SPHK1 is a member of sphingosine kinases (SPHKs), and its abnormal expression has been correlated with poor prognosis and clinicopathological features in cancer patients. Growing evidence points to SPHK1's involvement in cellular resistance to chemotherapy, as well as its role in tumor progression, metastasis, and cancer cell survival. Mechanistically, SPHK1 catalyzes the formation of sphingosine-1-phosphate (S1P), a potent signaling lipid that promotes angiogenesis, metastasis, immune evasion, and survival through S1PR-mediated pathways. Reducing SPHK1 expression through genetic silencing or pharmacological inhibition has been shown in recent research to lessen drug resistance in cancer cells, suggesting that SPHK1 is a potential target for anticancer therapies. For example, SPHK1 inhibitors and anti-S1P monoclonal antibodies could enhance the efficacy of doxorubicin in breast cancer, docetaxel in prostate cancer, and gemcitabine in pancreatic cancer. This review aims to provide a detailed description of the structure and molecular mechanisms that regulate SPHK1. Additionally, we review the interaction between SPHK1 signaling and drug resistance mechanisms separately in various cancers, including breast, gynecological, esophageal, nasopharyngeal, lung, liver, pancreatic, gastric, and colorectal cancers. Finally, we discuss the prospects and challenges of SPHK1 regulation as a therapeutic strategy in resistant cancer therapy. We anticipate that our review will offer valuable insights and provide a foundation for future research.</p> Graphical Abstract <p></p>