Complicated skin and skin-structure infections (cSSSIs) are among the most common infections treated in the hospital setting. They are a significant clinical problem, partially owing to increasing resistance of infecting bacteria to current antibiotic therapies (nosocomial and community-acquired methicillin-resistant Staphylococcus aureus, extended spectrum beta-lactamase-producing-Enterobacteriaceae, and multidrug-resistant [MDR] Pseudomonas aeruginosa, among others). The optimal choice of antibacterial therapy among the few available options for infections caused by MDR pathogens is fundamental to maximize clinical effectiveness and minimize the likelihood of further resistance development. Few antimicrobial agents are currently available to treat MDR bacteria in cSSSIs. In this context, the use of new antibiotic agents (i.e., linezolid, daptomycin and tigecycline) and the optimization of the pharmacodynamic targets of classic antibiotics (i.e., carbapenems) is one potential solution to these problems, and some of these agents are highlighted in this article. The purpose of this article is to provide clinicians with an evidence-based review of MDR pathogens causing cSSSIs, the implications of resistance to currently used drug therapy, and to identify new therapeutic options for resistant pathogens causing cSSSIs.