AbstractThe BRICHOS protein superfamily is a diverse group of proteins associated with a wide variety of human diseases, including respiratory distress, COVID‐19, dementia, and cancer. A key characteristic of these proteins—besides their BRICHOS domain present in the ER lumen/extracellular part—is that they harbor an aggregation‐prone region, which the BRICHOS domain is proposed to chaperone during biosynthesis. All so far studied BRICHOS domains modulate the aggregation pathway of various amyloid‐forming substrates, but not all of them can keep denaturing proteins in a folding‐competent state, in a similar manner as small heat shock proteins. Current evidence suggests that the ability to interfere with the aggregation pathways of substrates with entirely different end‐point structures is dictated by BRICHOS quaternary structure as well as specific surface motifs. This review aims to provide an overview of the BRICHOS protein family and a perspective of the diverse molecular chaperone‐like functions of various BRICHOS domains in relation to their structure and conformational plasticity. Furthermore, we speculate about the physiological implication of the diverse molecular chaperone functions and discuss the possibility to use the BRICHOS domain as a blood–brain barrier permeable molecular chaperone treatment of protein aggregation disorders.