Nonfermentative gram-negative bacilli are still a major concern in compromised individuals. By far the most important of these organisms is Pseudomonas aeruginosa, although Acinetobacter baumannii (previously Acinetobacter calcoaceticus), Stenotrophomonas maltophilia (previously Pseudomonas and Xanthomonas maltophilia), and Burkholderia cepacia (previously Pseudomonas cepacia) are also of substantative concern because of their similar high intrinsic resistances to antibiotics. The basis for the high intrinsic resistance of these organisms is the low outer-membrane permeability of these species, coupled with secondary resistance mechanisms such as an inducible cephalosporinase or antibiotic efflux pumps, which take advantage of low outer-membrane permeability. Even a small change in antibiotic susceptibility of these organisms can result in an increase in the MIC of a drug to a level that is greater than the clinically achievable level. In this review, the major mechanisms of resistance observed in the laboratory and clinic are summarized.