The European Union's attention to the problem of antibacterial resistance will soon reach a 10-year mark, but the rates of resistance in Gram-positive and Gram-negative bacteria are still increasing. This review focuses on the clinical impact of resistant Gram-positive bacteria on patients. Multiple drug resistance in pneumococcal infections will lead to more treatment failures and higher mortality, which so far have been seen with penicillins and pathogens with high-level resistance. Several studies have demonstrated higher mortality, prolonged length of hospital stay and higher costs associated with methicillin-resistant Staphylococcus aureus infections, in comparison with methicillin-susceptible Staphylococcus aureus infections. Similarly, vancomycin-resistant enterococci bloodstream infections have a negative impact with respect to mortality, length of hospital stay and costs, in comparison with infections due to vancomycin-susceptible enterococci. Several distinctive prophylactic and therapeutic approaches have to be undertaken to successfully prevent the clinical consequences of antibiotic resistance in Gram-positive bacteria. This review addresses the impact of antibiotic-resistant Gram-positive pathogens on clinical outcomes.