Cancer is becoming more common worldwide, impacting the vast majority of people. As a result, new anticancer drugs are currently being created, and their safety is still being assessed. Pyrazine-based medications are a substantial contribution, as they are one of the most important pharmacophores found in heterocyclic compounds both synthetically and naturally. It's a six-membered aromatic heterocycle with two nitrogen atoms with a wide range of therapeutic applications in drug development and numerous prospects for future enhancement in anticancer drugs by targeting several critical receptors. A number of pyrazine compounds have been shown to inhibit enzymes, receptors, and a range of additional cancer-fighting targets. Researchers are currently focused on the creation of pyrazine-based novel derivatives for cancer treatment in combination with other moieties. As a result, this review illuminates the recent therapeutic expansion of pyrazine-based drugs, as well as their synthetic schemes, tabulated detailed clinical trial drugs, marketed drugs with their primary target, and a list of recently patented and published research papers, all of which will help scientists build successful medications with the appropriate pharmacological activity.