Sphingosine 1-phosphate (S1P) and sphingosine kinase 1 (SphK1) play critical roles in cancer progression and chemoresistance. S1P is synthesized by SphK1 and SphK2, and its levels are elevated in various cancers, including ovarian, prostate, colorectal, breast, and hepatocellular carcinoma (HCC). S1P promotes cancer cell survival, metastasis, angiogenesis, and resistance to chemotherapy by activating various signaling pathways, such as ERK, PI3K/AKT, and MAPK. S1P also influences cell cycle progression, apoptosis, and EMT. SphK1 is overexpressed in many cancers and is associated with poor prognosis. Targeting the S1P/SphK1 pathway is a promising therapeutic strategy to overcome chemoresistance. S1P is transported across cell membranes via ABC transporters and Spns2, and it binds to G-protein-coupled receptors (S1PR1-5), which mediate its biological effects. S1P has diverse functions, including anti-apoptotic effects, angiogenesis, and immune modulation. It is also involved in cardiovascular diseases, neuroinflammation, and neurodegenerative disorders. S1P can be produced in the nucleus and cytoplasm, and its levels are regulated by enzymes such as S1P lyase and S1P phosphatases. Several SphK1 inhibitors have been developed, including PF-543, SK1-I, and LCL351. These inhibitors reduce S1P production, inhibit cancer cell proliferation, and enhance chemosensitivity. SphK1 inhibitors show promise in overcoming chemoresistance by modulating signaling pathways involved in cell survival, migration, and metastasis. The most effective inhibitors, such as LCL351 and SLR080811, demonstrate high selectivity for SphK2 and significant anti-cancer activity. These inhibitors reduce S1P levels, increase ceramide, and inhibit tumor growth. SphK1 inhibitors are being evaluated for their potential as therapeutic agents in cancer treatment.Sphingosine 1-phosphate (S1P) and sphingosine kinase 1 (SphK1) play critical roles in cancer progression and chemoresistance. S1P is synthesized by SphK1 and SphK2, and its levels are elevated in various cancers, including ovarian, prostate, colorectal, breast, and hepatocellular carcinoma (HCC). S1P promotes cancer cell survival, metastasis, angiogenesis, and resistance to chemotherapy by activating various signaling pathways, such as ERK, PI3K/AKT, and MAPK. S1P also influences cell cycle progression, apoptosis, and EMT. SphK1 is overexpressed in many cancers and is associated with poor prognosis. Targeting the S1P/SphK1 pathway is a promising therapeutic strategy to overcome chemoresistance. S1P is transported across cell membranes via ABC transporters and Spns2, and it binds to G-protein-coupled receptors (S1PR1-5), which mediate its biological effects. S1P has diverse functions, including anti-apoptotic effects, angiogenesis, and immune modulation. It is also involved in cardiovascular diseases, neuroinflammation, and neurodegenerative disorders. S1P can be produced in the nucleus and cytoplasm, and its levels are regulated by enzymes such as S1P lyase and S1P phosphatases. Several SphK1 inhibitors have been developed, including PF-543, SK1-I, and LCL351. These inhibitors reduce S1P production, inhibit cancer cell proliferation, and enhance chemosensitivity. SphK1 inhibitors show promise in overcoming chemoresistance by modulating signaling pathways involved in cell survival, migration, and metastasis. The most effective inhibitors, such as LCL351 and SLR080811, demonstrate high selectivity for SphK2 and significant anti-cancer activity. These inhibitors reduce S1P levels, increase ceramide, and inhibit tumor growth. SphK1 inhibitors are being evaluated for their potential as therapeutic agents in cancer treatment.