Abstract: Pyrimido [5, 4-c] quinolone derivatives are significant synthetic targets that show numerous interesting biological activities. The pyrimido [4, 5-b] quinoline is the most famous source of these derivatives, which has been used in medicine to antitumor and target different diseases. Since the segregation of quinoline derivatives, many synthetic methodologies were advanced for their synthesis. Despite the current interesting findings on this class of pyrimidoquinoline, the chemical literature deficits a comprehensive summary of the synthetic methodologies and biological activities of pyrimido [5, 4-c] quinoline derivatives. This review focuses on recent advances in pyrimido [5, 4-c] quinolines chemistry via debating diverse synthetic ways developed for the preparation of pyrimido [5, 4-c] quinolines and other unique derivatives that exhibited promising biological activities. Also, it sheds light on the most widespread reactions of pyrimidoquinolines and the employment of these derivatives as the essential building blocks for different biologically active compounds:. Among these reactions used to prepare pyrimido [5, 4-c] quinoline derivatives are the following: Biginelli-type one or three-component reaction, Micheal addition, intermolecular cyclization, cyclo-condensation, acylation, Vielsmeir formylation, Suzuki cross-coupling reaction, transformation, oxidation-reduction, esterification, dehydration, decarboxylation, methylation, chlorination, alkylation.