Stenotrophomonas maltophilia has emerged in recent years as a paradigm of an intrinsically resistant, opportunistic bacterial pathogen with an environmental origin. The recent publication of the sequences of two S. maltophilia genomes has shown that this bacterium contains a large repertoire of antibiotic resistance determinants, probably contributing to its characteristic susceptibility to antibiotics. Among those determinants, the best characterized are a number of multidrug efflux pumps, beta-lactamases and aminoglycoside-inactivating enzymes. Recently, the presence of a gene coding for a Qnr determinant in the genome of S. maltophilia has also been described. Together, these elements confer resistance to several of the drugs currently used for treating infections. Besides these chromosomally encoded determinants, which evolved in S. maltophilia long before the recent human use of antibiotics, this bacterial species is acquiring novel resistance genes by horizontal gene transfer, thereby increasing its resistance. Future studies are required to fully understand the mechanisms of resistance, their regulation and potential crosstalk with S. maltophilia virulence, as well as the population dynamics of the different isolates of this bacterial species.