Protein misfolding is associated with several human diseases, including Alzheimer's, and can hinder the efficient production of soluble recombinant proteins. In this issue, Wigley et al. (see p. 131) present a method for assessing the solubility and folding of expressed proteins in vivo. The assay is based on the generation of functional β-galactosidase (β-gal) in Escherichia coli by complementation of two fragments of the enzyme. By fusing one of the fragments to the C terminus of a target protein, such as Aβ, the Alzheimer's amyloid peptide, the generation of functional β-gal is made dependent on the solubility of the fusion protein. Enzyme activity is monitored by a color change. The assay should be applicable to screening for drugs that promote the folding or inhibit the aggregation of disease-related proteins (see also p. 112).