Infections due to multidrug resistant (MDR) pathogens are among the major threats in critically ill patients. Reduced vancomycin susceptibility in Staphylococcus aureus, high-level aminoglycoside resistance in enterococci, extended spectrum beta-lactamase and carbapenemases production in Enterobacteriaceae, carbapenem and colistin resistance in Pseudomonas spp. and Acinetobacter spp. are increasing in many intensive care units around the world. In the last few years some new anti-Gram-positive agents have been developed, whereas for Gram-negatives the available options are very limited. Infections control and antimicrobial stewardship programs are currently the only available options to avoid a further increase of these pathogens.