The process of folding is a seminal event in the life of a protein, converting a newly synthesized polypeptide into the functional three-dimensional conformation thermodynamically encoded by its amino acid sequence. Incorrect folding or misfolding, can not only lead to the loss of this function but also to the accumulation of protein aggregates–insoluble deposits of polypeptides. Aggregates are a hallmark of stressed, aged, and disease-state cells and pose a danger not only after they have accumulated but also during the process of their formation. Cell health therefore heavily depends on the ability to prevent protein aggregation.

It is unsurprising, then, that a number of distinct biological processes have evolved to protect cells from the deleterious effects of aggregates. These involve aiding proper folding, sequestering misfolded and aggregation-prone species, and even the dissolution and clearance of already-formed protein aggregates, carried out by a specialized group of proteins termed molecular chaperones [1,2]. Here we will focus on recent advancements in our mechanistic understanding of protein disaggregases–the chaperone machines that can reverse aggregation, restoring proteins to their native structure, function, and localization.