<p>Acylglycerol kinase (AGK) is a mitochondrial lipid kinase that has garnered significant interest due to its crucial involvement in cancer biology. Initially identified for its enzymatic transformation of monoacylglycerol and diacylglycerol into lysophosphatidic acid (LPA) and phosphatidic acid (PA), AGK has subsequently been associated with a wide array of carcinogenic mechanisms. These include the regulation of tumor cell proliferation, mitochondrial dynamics, cancer stem cell maintenance, immune evasion, and metastatic progression. AGK activates key signaling cascades, i.e., PI3K/AKT/mTOR, JAK2/STAT3, and NF-κB, that are associated with tumor growth and resistance to therapy. Moreover, its elevated expression in diverse malignancies correlates with poor prognosis and therapeutic failure, positioning AGK as both a biomarker and a potential therapeutic target. Preclinical studies indicate that AGK inhibition, by either small drugs such as Netupitant or gene-silencing techniques, can hinder tumor development and enhance therapy sensitivity. This review consolidates the most recent insights into AGK’s molecular functions, its pathophysiological implications in cancer, and its novel treatment ramifications. The discussion encompassed the existing trial paradigms and proposed pathways for the future of clinical translation. This report emphasizes the need for focused research and clinical evaluation of AGK within the advancing framework of precision oncology.</p> Graphical Abstract <p>Dual functional roles of Acylglycerol Kinase (AGK) in cancer and its therapeutic targeting.</p>