The rationale behind drug design is the strategic utilization of heterocyclic fragments with specific physicochemical properties to form molecular targeted agents. Among the heterocyclic molecules, pyrimidine has proved to be a privileged pharmacophore for various biological cancer targets. The anti-cancer potential of small molecules with fused and substituted pyrimidines can be enhanced through bioisosteric replacements and altering their ADME parameters. Although several small molecules are used in cancer chemotherapy, oncology therapeutics has various limitations, especially in their routes of administration and their concurrent side effects. Such pernicious effects may be overcome, via selective biological targeting. In this review, the biological targets, to inhibit cancer, have been discussed. The structural activity relationship of fused and substituted pyrimidines was studied. Eco-friendly synthetic approaches for pyrimidine derivatives have also been discussed. This review will give an insight to scientists and researchers of medicinal chemistry discipline to design small molecules having a pyrimidine scaffold with high anti-cancer potential.