Nalidixic acid was the first quinolone antibiotic introduced to the treatment of urinary tract infections. It was effective especially against Gram-positive and Gram-negative bacteria but resistance to it emerged rapidly. In this article we reviewed the newly synthesized nalidixic acid based compounds as effective antibacterial, antitubercular and antifungal agents. We mainly focused on the effect of various chemical structure modifications of nalidixic acid on the antimicrobial activity of its derivatives. These newly synthesized compounds may serve as lead structures for the design of more specific, efficacious, affordable drugs, particularly active against resistant microorganisms.