At the Cold Spring Harbor Meeting on 'Molecular Chaperones and the Heat Shock Response' in May 1996, Susan Lindquist presented evidence that a chaperone of yeast termed Hsp104, which her group had been investigating for several years, is able to dissolve protein aggregates (Glover, J.R., Lindquist, S., 1998. Hsp104, Hsp70, and Hsp40: a novel chaperone system that rescues previously aggregated proteins. Cell 94, 73-82). Among many of the participants this news stimulated reactions reaching from decided skepticism to utter disbelief because protein aggregation was widely considered to be an irreversible process. Several years and publications later, it is undeniable that Susan had been right. Hsp104 is an ATP dependent molecular machine that-in cooperation with Hsp70 and Hsp40-extracts polypeptide chains from protein aggregates and facilitates their refolding, although the molecular details of this process are still poorly understood. Meanwhile, close homologues of Hsp104 have been identified in bacteria (ClpB), in mitochondria (Hsp78), and in the cytosol of plants (Hsp101), but intriguingly not in the cytosol of animal cells (Mosser, D.D., Ho, S., Glover, J.R., 2004. Saccharomyces cerevisiae Hsp104 enhances the chaperone capacity of human cells and inhibits heat stress-induced proapoptotic signaling. Biochemistry 43, 8107-8115). Observations that Hsp104 plays an essential role in the maintenance of yeast prions (see review by James Shorter in this issue) have attracted even more attention to the molecular mechanism of this ATP dependent chaperone (Chernoff, Y.O., Lindquist, S.L., Ono, B., Inge-Vechtomov, S.G., Liebman, S.W., 1995. Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factor [PSI+]. Science 268, 880-884).