Multiresistant Gram-positive cocci, including Staphylococcus aureus, the group of coagulase-negative staphylococci, Enterococcus faecalis and Enterococcus faecium, as well as Streptococcus pneumoniae and other streptococci, represent emerging pathogens in the community, but especially in the setting of immunocompromised, hospitalized patients. In these last subjects, it happens in particular when surgery, invasive procedures, or prosthetic implants are of concern, patients are admitted in intensive care units, or underlying chronic disorders and immunodeficiency are of concern, and broad-spectrum antibiotics are widely used in the environment. The spectrum of antimicrobial compounds now available for an effective management and treatment of these relevant infections is significantly threatened by the emerging and spread of methicillin-resistant and more recently glycopeptide-resistant microbial strains. The streptogramine association represented by quinupristin/dalfopristin, the oxazolidinone derivative linezolid, and the recently licensed daptomycin and tigecycline, together with a number of glycopeptides, quinolones, and other experimental compounds on the pipeline, represent an effective response to the majority of these problems, due to their innovative mechanisms of action, their maintained or enhanced activity against multiresistant pathogens, their effective pharmacokinetic/pharmacodynamic properties, their frequent possibility of synergistic activity with other compounds effective against Gram-positive pathogens, and a diffuse potential for a safe and easy administration, also to compromised patients. The main problems related to the epidemiology of multiresistant gram-positive infection, the potential clinical indications of all recently available compounds compared with the standard of care of treatment of resistant Gram-positive infections, and updated data on efficacy and tolerability of all these compounds, are updated and outlined based on an extensive review of all available, recent evidences from the international literature.