Peptides bound or linked to heat-shock proteins (HSPs) of microbial or mammalian origin have been shown to elicit potent antigen-specific immunity. Some members of the HSP family, such as hsp60, hsp70, hsp90 and gp96, are able also to stimulate cells of the innate immune system directly and thus, act as ‘danger'-signaling molecules. This effect is independent of HSP-associated peptides and, in many respects, resembles the effect of lipopolysaccharide (LPS). Here, we discuss the similarities between the responses to HSPs and LPS and also, emphasize that care must be taken when working with preparations of HSPs in experimental settings and interpreting experimental data.