Macrolides, such as clarithromycin and azithromycin, having good activity against pathogens such as Legionella, Chlamydia, Campylobacter spp, Branhamella spp, Pasteurella multocida and streptococci, have gained wide acceptance for the treatment of both upper and lower respiratory tracts, as well as cutaneous infections. Emergence of bacterial resistance, particularly in gram-positive bacteria, has been observed. Macrolide-resistant Streptococcus pneumoniae and S. pyogenes are found in France and many other countries, resulting in failure of therapy for pneumonia, pharyngitis, and skin infection. RU 004, HMR 3647, and TE 802 were reported to be active against these resistant strains. Research at Abbott produced several macrolide derivatives in the anhydrolide, tricyclic and tetracyclic ketolides as well as 6-O-alkyl ketolides series having potent activity against macrolide resistant S. pyogenes and S. pneumoniae. Research on streptogramins to overcome bacterial resistance in gram-positive bacteria has produced interesting compounds. Another class of antibacterial agent called quinolones is useful for the treatment of bacterial infections of respiratory tract, urinary tract, skin and soft tissues, as well as sexually transmitted diseases. Ciprofloxacin, the market leader, however, has low potency against anaerobes. Bacterial resistance ( such as Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus ) to ciprofloxacin is increasing rapidly. Many quinolone compounds are being synthesized to address these drawbacks. The new quinolones currently under development are characterized by enhanced activities against streptococci, staphylococci, enterococci, and anaerobes. This presentation reviews the current research in the identification of agents to overcome the macrolide and quinolone resistance.