Melioidosis is an infectious disease endemic in tropical and subtropical areas but is most often described in Southeast Asia and northern Australia. It has increasingly gained attention in the Western Hemisphere because of its potential use as a biological weapon. Progress in our understanding of the virulence mechanisms of Burkholderia pseudomallei, the causative agent, has provided clues to the pathogenesis of the disease. The bacterium can remain latent in the body for long periods of time and also possesses mechanisms to evade the host immune response. The complex spectrum of clinical manifestations resulting from infection could reflect the various outcomes after the host immune response encounters the bacteria. The use of appropriate animal models of susceptibility will likely shed light on what determines the development of an acute, chronic, or latent infection.