The incidence of Gram-positive bloodstream infections has been increasing steadily. The virulence of coagulase-negative staphylococci is based mainly on their ability to produce biofilms, and thus cause infections of intravascular devices and foreign bodies, which must be removed to resolve the infection. Staphylococcus aureus is the leading cause of endocarditis, and it is important to recognize patients at risk of the complications of S. aureus bloodstream infections. The rate of meticillin resistance is higher in healthcare-related infections, although clones of community-acquired meticillin-resistant S. aureus carrying the Panton-Valentine leukocidin have recently emerged. Vancomycin minimum inhibitory concentration (MIC) creep gives cause for concern, and MICs >1 microg/mL are associated with higher failure rates and mortality in patients with S. aureus bacteraemia treated with vancomycin. Daptomycin should be considered the optimal empirical treatment for S. aureus bloodstream infections in settings with medium to high prevalence of meticillin-resistant Staphylococcus aureus infections. Enterococci are the third leading cause of Gram-positive bacteraemia in our institution. Management of this disease is difficult because of its intrinsic resistance to antibiotics, mainly in Enterococcus faecium infections. The recently described synergism of ampicillin plus ceftriaxone is a good therapeutic option for Enterococcus faecalis bacteraemia and endocarditis caused by high-level aminoglycoside-resistant strains.