Gram-positive bacteria are responsible for a broad range of infectious diseases, and the emergency and wide spread of drug-resistant Gram-positive pathogens including MRSA and MRSE has caused great concern throughout the world. 4-Quinolones which are exemplified by fluoroquinolones are mainstays of chemotherapy against various bacterial infections including Gram-positive pathogen infections, and their value and role in the treatment of bacterial infections continues to expand. However, the resistance of Gram-positive organisms to 4-quinolones develops rapidly and spreads widely, making them more and more ineffective. To overcome the resistance and reduce the toxicity, numerous of 4-quinolone derivatives were synthesized and screened for their in vitro and in vivo activities against Gram-positive pathogens, and some of them exhibited excellent potency. This review aims to outlines the recent advances made towards the discovery of 4-quinolone-based derivatives as anti-Gram-positive pathogens agents and the critical aspects of design as well as the structure-activity relationship of these derivatives. The enriched SAR paves the way to the further rational development of 4-quinolones with a unique mechanism of action different from that of the currently used drugs to overcome the resistance, well-tolerated and low toxic profiles.