Caveolae and lipid rafts are increasingly being recognized as a significant portal of entry into host cells for a wide variety of pathogenic microorganisms. Entry through this mechanism appears to afford the microbes protection from degradation in lysosomes, though the level to which each microbe actively participates in avoiding lysosomal fusion may vary. Other possible variations in microbial entry through caveolae or lipid rafts may include (i) the destination of trafficking after entry and (ii) how actively the microbe contributes to the caveolae lipid/raft mediated entry. It seems that, though a wide variety of microorganisms are capable of utilizing caveolae/lipid rafts in various stages of their intracellular lifestyle, there can be distinct differences in how each microbe interacts with these structures. By studying these variations, we may learn more about the normal functioning of these cellular microdomains, and perhaps of more immediate importance, how to incorporate the use of these structures into the treatment of both infectious and non-infectious disease.