Here we report the genetic and proposed molecular basis for silver resistance in pathogenic microorganisms. The silver resistance determinant from a hospital burn ward Salmonella plasmid contains nine open reading frames, arranged in three measured and divergently transcribed RNAs. The resistance determinant encodes a periplasmic silver-specific binding protein (SilE) plus apparently two parallel efflux pumps: one, a P-type ATPase (SilP); the other, a membrane potential-dependent three-polypeptide cation/proton antiporter (SilCBA). The sil determinant is governed by a two-component membrane sensor and transcriptional responder comprising silS and silR, which are co-transcribed. The availability of the sil silver-resistance determinant will be the basis for mechanistic molecular and biochemical studies as well as molecular epidemiology of silver resistance in clinical settings in which silver is used as a biocide.