The recent emergence of numerous aerobic and anaerobic beta-lactamase-producing bacterial strains has been associated with an increase in the failure rate of penicillins in the therapy of infection caused by these organisms. These include respiratory tract, skin of soft tissue, female genital tract, intra-abdominal, and other miscellaneous infections. The important aerobic beta-lactamase-producing bacteria (BLPB) include Staphylococcus aureus, Branhamella catarrhalis, Haemophilus sp., Neisseria gonorrhoeae, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Legionella sp. The anaerobic BLPB are all Bacteroidiaceae and include Bacteroides fragilis group, B. melaninogenicus group, B. oralis, B. oris-buccae, and Fusobacterium sp. Laboratory, animal, and clinical studies that support the indirect pathogenicity of these organisms and the distribution of these BLPB in various infections are reviewed. BLPB may not only have a direct pathogenic role in causing the infection, but also an indirect pathogenic role. The indirect pathogenicity of these organisms is apparent through their ability not only to survive penicillin therapy, but also to protect penicillin-susceptible pathogens from that drug. These direct and indirect virulence characteristics of aerobic and anaerobic BLPB require the administration of appropriate antimicrobial therapy directed against all pathogens in mixed infections.