A number of different mechanisms of macrolide resistance have been described in Gram-negative bacteria. These include 16 acquired genes (esterases, phosphorylases, rRNA methylases, and effluxes) and include those thought to be unique to Gram-negative bacteria (both esterases and two of the phosphorylases) and those shared with Gram-positive bacteria (one phosphorylase) and those primarily of Gram-positive origin (rRNA methylases and efflux genes). In addition, mutations, which modify the 23S rRNA, ribosomal proteins L4 and / or L22, and / or changes in expression of innate efflux systems which occur by missense, deletion and / or insertion events have been described in five Gramnegative groups, while an innate transferase conferring resistance to streptogramin A has been identified in a sixth genus. However, the amount of information on both acquisition and mutations leading to macrolide, lincosamides, streptogramins, ketolides and oxazolidinones (MLSKO) resistance is limited. As a consequence this review likely underestimates the true distribution of acquired genes and mutations in Gram-negative bacteria. As use of these drugs increases, it is likely that interaction between members of the MLSKO antibiotic family and Gram-negative bacteria will continue to change resistance to these antibiotics; by mutations of existing genes as well as by acquisition and perhaps mutations of acquired resistant genes in these organisms and more work needs to be done to get a clearer picture of what is in the Gram-negative population now, such that changes can be monitored.