Hsp90 is a dimeric molecular chaperone that contributes to signal transduction by stabilizing a large number of client proteins directly involved in signaling pathways. During client processing, ATP binds to Hsp90 and drives huge conformational changes in the chaperone that ultimately lead to ATP hydrolysis (Figure 1). A defined sequence of conformational rearrangements is required to complete one cycle of ATP hydrolysis. To date, the potentially most critical conformational change was resolved by the crystal structure of yeast Hsp90, which shows AMP-PNP, a nonhydrolysable ATP analog, bound to Hsp90 in the N-terminally dimerized conformation and complexed with the cochaperone Sba1/p23 (Ali et al., 2006). Another important piece of the puzzle is provided by the structure of HtpG, the bacterial Hsp90 homolog, which was crystallized recently and shows an N-terminal open conformation in the absence of nucleotide (Shiau et al., 2006). These crystal structures extended our view of the Hsp90 machine and confirmed earlier suggestions of common mechanistic steps within the Hsp90 family. Now, Gewirth and coworkers (Dollins et al., 2007) present a crystallographic analysis of the endoplasmic reticulum Hsp90-homolog Grp94.