Group A streptococcus and Staphylococcus aureus are the most common bacterial etiologies of skin and soft tissue infections that range in virulence from very mild to limb/life threatening. Antibiotic coverage recommendations are varying and subject to controversy. Antibiotic resistance patterns are evolving with many different biochemical mechanisms. Rapid bacterial identification using mass spectrometry is on the horizon. Therapeutic considerations should include cost and adherence issues.