Epidemiology and clinical manifestations of nosocomial infections have been progressively evolving through last three decades. New pathogens, often associated to multiple antibiotic-resistances, are now among the leading etiologies in a patient population mainly represented by individuals debilitated by serious underlying diseases, immunosuppressive treatments and multiple diagnostic and therapeutic invasive procedures. Under these circumstances, when an infectious complication develops, prompt initiation of empiric antibiotic therapy, based on general and/or local epidemiology of nosocomial infections, may be crucial for survival of more critically ill patients. Based on recent data, the antibiotics of choice for treatment of nosocomial infections should have not only a bactericidal activity and a broad antibacterial spectrum, but also poor propensity to induce antibiotic-resistance and a satisfactory pharmacoeconomy profile. After a detailed description of the above mentioned context, the pre-eminent role of piperacillin-tazobactam in the treatment of nosocomial infections is reviewed and discussed.