Cells are equipped with protein quality control pathways in order to maintain a healthy proteome; a process known as protein homeostasis. Dysfunction in protein homeostasis leads to the development of many diseases that are associated with proteinopathies. Recently, the rhomboid superfamily has attracted much attention concerning their involvement in protein homeostasis. While their functional role has become much clearer in the last few years, their systemic significance in mammals remains elusive. Here we delineate the current knowledge of rhomboids in protein quality control and how these functions are integrated at the organismal level.