Skin and soft tissue infections (SSTIs) are among the most common infections in outpatients and the most frequent infectious cause of referrals to emergency departments in developed world, contributing to significant morbidity and healthcare expenditures. We sought to review recent literature covering epidemiology of SSTIs. Staphylococcus aureus and streptococci predominate and methicillin-resistant S. aureus (MRSA) poses additional challenges; community-acquired-MRSA in some areas is superseding methicillin-susceptible S. aureus and multidrug resistance is evolving. Incidence data of SSTIs from United States show a decreasing trend, whereas trends of hospitalization rates were increasing. Despite low mortality associated with SSTIs, high rates of treatment failure and relapses are of concern. Diagnosis and management decisions in the emergency department (ED) lack validated tools for prediction of clinical response particularly among elderly, immunocompromised, obese, and patients with comorbidities. A variety of modifiable and nonmodifiable risk factors of the host and data from local epidemiology should be considered to prevent recurrence and treatment failure. An evolving epidemiology of SSTIs make microbiologic documentation and surveillance of local data imperative. New assessment algorithms with potential use in the ED are a priority. The universal applicability of international guidelines is questioned in this setting.