Proteasome inhibitors (PI) have evolved as the central backbone of treatment for multiple myeloma (MM), with first-in-class bortezomib and second- and third-generation PI, carfilzomib and ixazomib, having been approved for this indication. Proteasome inhibition disrupts the unfolded protein response to resolve excessive endoplasmic reticulum stress, but also leads to massive metabolic changes manifested by the induction of amino acid biosynthesis, an anti-oxidant response, lipogenesis and an increase in protein folding. In this sense, PI represent a unique class of drugs targeting cancer cell metabolism by affecting the balance between protein biosynthesis, folding and destruction. However, the adaptive changes in MM cell metabolism may provide the basis of resistance to PI, as high glycolytic activity or rewiring glucose metabolism is associated with bortezomib resistance in MM.