Transport into the endoplasmic reticulum (ER) is the crucial step in the biosynthesis of most secretory proteins and many membrane proteins. The products of the SIL1, SEC62 and SEC63 genes act in concert with the SEC61 complex and the molecular chaperones BiP and GRP170 to transport proteins into the ER. Interestingly, recent genetic work has linked mutations in the human and murine SIL1 genes to neurodegeneration, and mutations in the human SEC63 gene to autosomal dominant polycystic liver disease. Furthermore, mutations in the SEC63 gene and overexpression of the SEC62 gene are associated with various human cancers. Therefore, we suggest that these diseases should be considered to be pathologies of protein transport into the ER rather than protein-folding diseases.