A common limitation of recombinant protein production in bacteria is the formation of insoluble protein aggregates known as inclusion bodies. The propensity of a given protein to aggregate is unpredictable, and the goal of a properly folded, soluble species has been pursued using four main approaches: modification of the protein sequence; increasing the availability of folding assistant proteins; increasing the performance of the translation machinery; and minimizing physicochemical conditions favoring conformational stress and aggregation. From a molecular point of view, inclusion bodies are considered to be formed by unspecific hydrophobic interactions between disorderly deposited polypeptides, and are observed as 'molecular dust-balls' in productive cells. However, recent data suggest that these protein aggregates might be a reservoir of alternative conformational states, their formation being no less specific than the acquisition of the native-state structure. © 2006 Elsevier Ltd. All rights reserved.