Multi-antibiotic resistant Gram-positive cocci, which include Staphylococcus aureus, the coagulase-negative staphylococcal group, Enterococcus faecalis and Enterococcus faecium, and other streptococci, represent emerging pathogens especially in the setting of the immunocompromised, hospitalized patients, 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 or immunosuppressive drugs are widely administered. During the recent years, the phenomenon of multiresistant Gram-positive cocci is spreading to the community, where the retrieval of such microorganism is progressively increasing. The spectrum of available antimicrobial compounds for an effective management of these relevant infections is significantly impaired in selection and clinical efficacy by the emerging and spread of methicillin-resistant and more recently glycopeptide-resistant Gram-positive microbial strains. The first oxazolidinone derivative linezolid, together with the recently licensed quinupristin-dalfopristin, daptomycin, and tigecycline, followed by a number of glycopeptides, fluoroquinolones, and other experimental compounds on the pipeline, represent an effective response to the great majority of these concerns, 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 when compromised patients are of concern. The main problems related to the epidemiological and clinical features 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 linezolid as the golden standard compound for vancomycin-resistant Gram-positive cocci in multiple clinical situations, are outlined and updated on the ground of an extensive review of all the available, recent evidences coming from the international literature.