Skin and soft tissue infections (SSTIs) are a broad spectrum of diseases, including uncomplicated and complicated infections. Herein, we review the current epidemiology and microbiology of SSTIs. In the last decades, a significant growing trend of SSTIs both in the community and healthcare settings with a dramatic increase of the economic burden for these diagnoses was observed. Several observational studies found that SSTIs are a substantial cause of ambulatory and emergency department visits, and of hospitalizations. Although, microbiology of SSTIs changes according to the clinical feature and the severity of illness, Staphylococcus aureus being the leading cause of both uncomplicated infections and complicated infections. Moreover, the increasing prevalence of infections because of multidrug-resistant bacteria, mainly methicillin-resistant S. aureus (both community-acquired and healthcare-associated methicillin-resistant S. aureus), are associated with significantly increased morbidity, mortality, length of hospital stay, and costs, compared with infections because of susceptible strains. Moreover, although it is unclear whether high vancomycin minimum inhibitory concentration is associated with a worse outcome, it poses a further challenge for the clinicians. The understanding of the current epidemiology and microbiology of SSTIs is indicated for an appropriate antimicrobial therapy and an overall optimal management of SSTIs.