It is known that protein misfolding is governed by the hydrophobic effect of solutes at hydrophobic amino acid side chains. The hydrophobic force of nonaqueous solutes acts as a driving force for the spatial rearrangement of protein side chains, whose structural transitions need to be regulated in both time and space. Smaller hydrophobic solutes exert more effect at protein side chains, which involves the clustering of proteins into misfolded shapes. The consequences of misfolding are loss of protein function, gain of toxic function, or both. This is a physical process, whose result has been directly linked to a large number of human diseases.