Antibiotic resistance is an ever-increasing concern in the treatment of severe skin and skin-structure infections, pneumonia, bacteremia and other serious infections caused by methicillin-resistant Staphylococcus aureus, vancomycin-resistant S. aureus, group A Streptococcus and vancomycin-resistant Enterococcus. In this review, we summarize the current status of both US FDA-approved and investigational agents aimed at this group of pathogens. We also describe, in detail, the chemistry, mechanism of action, pharmacokinetic properties and spectrum of microbiological activity of iclaprim, a novel dihydrofolate reductase inhibitor recently awarded fast-track approval status by the FDA. Finally, we review the clinical efficacy of iclaprim compared with linezolid for skin and skin-structure infections as demonstrated in Phase III randomized, controlled trials, and comment on its potential role in the treatment of other severe infections with drug-resistant Gram-positive pathogens.