<p>Cancer remains a formidable challenge to global healthcare, necessitating the continuous exploration of novel therapeutic strategies. Pyrimidinetriones and their derivatives have emerged as a promising class of compounds with potent anticancer properties, presenting a new horizon in cancer treatment research. This review delves into the synthesis, structural modifications, and structure-activity relationships (SAR) of pyrimidinetriones in their role as anticancer agents. The synthesis of pyrimidinetriones involves versatile methodologies, including photochemical synthesis, multicomponent reactions, and microwave-assisted synthesis, providing facile access to diverse structural analogs. Structural modifications at various positions on the pyrimidine ring and the trione moiety have been explored to enhance the anticancer activity and selectivity of these compounds. Pyrimidinetriones exhibit multifaceted mechanisms of action against cancer cells, including inhibition of key enzymes, interference with signaling pathways, induction of apoptosis, and disruption of DNA replication and repair processes. Furthermore, their ability to overcome multidrug resistance mechanisms makes them particularly attractive for combating refractory cancers. The SAR studies have elucidated critical structural features governing the potency, selectivity, and pharmacokinetic properties of pyrimidinetriones. Through systematic SAR investigations, valuable insights have been gained into the optimal substitution patterns, stereochemical configurations, and physicochemical properties required for achieving enhanced anticancer efficacy.</p> Graphical Abstract <p></p>