A number of neurodegenerative disorders are associated with the formation and accumulation of protein aggregates in neurons. The underlying causes for aggregation are varied and include the expansion of CAG repeats within coding sequences that give rise to aberrant polypeptides containing polyglutamine (polyQ) tracts. In general, the pathological phenotype of polyQ disorders results from the disruption of several cellular processes, hence preventing the accumulation of misfolded proteins is likely to be the most effective therapeutic intervention. In the case of spinobulbar muscular atrophy (SBMA), an expanded polyQ tract encoded within the first exon of the androgen receptor (AR) gene results in hormone-dependent unfolding and formation of toxic AR oligomers. In a recent report, Wang et al. target the pathway through which polyQ-AR is normally degraded, with the intent of stimulating the process. It was previously shown that overexpression of the molecular chaperone Hsp70 promotes the clearance of polyQ-AR, although how exactly Hsp70 operates in this pathway remained poorly defined. In their study, the authors show that overexpression of Hip—a cochaperone that stabilizes Hsp70 in its ADP-dependent conformation and consequently increases substrate binding—promotes the clearance of polyQ-AR aggregates in a ubiquitin-dependent manner. Next, the ability of the small synthetic molecule YM-1, previously shown to bind the nucleotide-binding domain of Hsp70 in its ADP-bound (but not ATP-bound) state, was assayed for its ability to stimulate Hsp70 binding to unfolded substrates. The results demonstrate that YM-1, similarly to Hip, indeed favors Hsp70 in the ADP-bound, high–substrate-affinity state. Consistent with these observations, YM-1 diminished the cellular accumulation of polyQ-AR aggregates, and the induced clearance was inhibited by the proteasome inhibitor MG132, thus confirming the mechanism as proteasome dependent. Finally, the authors turned to a Drosophila melanogaster SMBA model to demonstrate the protective effect of YM-1 against polyQ-AR–induced toxicity in a physiologically relevant context. Although the potentially deleterious effects of YM-1 and similar molecules on other cellular processes remain to be assessed, this work suggests that allosteric activators of Hsp70 represent viable candidates for the treatment of several diseases with protein aggregation as their root cause. (Nat. Chem. Biol. doi:10.1038/nchembio.1140, published online 9 December 2012)