Protein homeostasis refers to regulating the functionality of every individual protein in the proteome. Proteins prone to misfolding present a particular challenge to cellular protein homeostasis and manipulating protein homeostasis factors with small molecules has emerged as a powerful therapeutic approach. A central protein homeostasis hub in a eukaryotic cell is the endoplasmic reticulum, which is the gateway for protein secretion. We aim to define molecular functions of cellular factors that facilitate protein homeostasis within the endoplasmic reticulum as well as to uncover small molecules that modulate proteostasis as potential new therapeutic strategies.