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PURPOSE OF REVIEW This article summarizes the available evidence enabling a stratification of risk for multidrug-resistant bacteria (MDRB) in patients with skin and soft tissue infection (SSTI). RECENT FINDINGS MDRB are increasingly reported in both healthcare-associated (HCA) and community-acquired (CA)-SSTI, including in patients with life-threatening presentations for whom early initiation of adequate antimicrobial therapy is pivotal to improve outcomes. Community-associated methicillin-resistant Staphylococcus aureus (MRSA) is now endemic in several geographical areas and may cause outbreaks in frail populations or other at-risk clusters. Pseudomonas aeruginosa and other nonfermenting Gram-negative pathogens are involved in CA-SSTI on an occasional basis, especially in patients with chronic wounds or recent antimicrobial exposure. The burden of HCA-SSTI because of MRSA, MR P. aeruginosa, MR Acinetobacter baumannii, extended-spectrum β-lactamase-producing Enterobacterales and vancomycin-resistant enterococci is amplifying in endemic settings. Severe comorbidities, prolonged hospitalization, invasive procedures, prior colonization or infection and antimicrobial exposure stand as the main risk factors for these conditions. Worryingly, carbapenemase-producing Enterobacterales are emerging as causative pathogens in HCA-SSTI. SUMMARY The choice of empirical agents depends on the type and location of SSTI, place of onset, initial severity and whether the patient presents or not with risk factors for MDRB, with local epidemiology and prior antimicrobial use being among the main features to consider.