Infections by multidrug resistant bacteria (MDR) occur frequently in patients admitted to intensive care unit (ICU) with incidence up to 40% in many world regions and are usually associated to high mortality. In ICU patients, numerous independent risk factors for infections by MDR bacteria have been identified whose careful management associated to an appropriate use of antibiotics are fundamental. Despite the latter may results challenging in many cases, combination of old and novel antibiotics usually permits to provide an in vitro effective strategy also in the more resistant strains. Nevertheless, as such antibiotic pressure produces harmful effects on microenvironment and immune response that render ICU patients prone to secondary or breakthrough infections by opportunistic agent. Beyond extensive antibiotic therapy, other factors as older age, chronic pathologies, trauma, surgery and persistent infections may cause ICU acquired immune suppression that involves both innate and adaptive immunity. Therefore, the approach to critically ill patients with sepsis caused by MDR infections should be based not only on the research for the best antibiotic strategy but also on the assessment and treatment of immune-dysfunction. Numerous promising immune-modulating therapy are under evaluation and we hope available in the close future.