Cancer, an intricate and formidable disease, continues to challenge Medical Science with its diverse manifestations and relentless progression. In the pursuit of novel therapeutic strategies, organic heterocyclic compounds have emerged as promising candidates due to their versatile chemical structures and intricate interactions with biological systems. Among these, pyrazine derivatives are characterized by a six-membered aromatic ring containing four carbon and two nitrogen atoms situated in a 1,4-orientation. These compounds garnered significant attention for their potential as anticancer agents. This comprehensive review provides a detailed analysis of the advancements made during this timeframe, encompassing the chemical diversity of pyrazine derivatives, their mechanisms of action at the cellular level, and structure-activity relationships, spanning the years 2010 to 2024. By examining their therapeutic potential, challenges, and future prospects, this review offers valuable insights into the evolving landscape of pyrazine derivatives as potent tools in the fight against cancer.