Multiple myeloma (MM) remains an incurable malignancy due to the acquisition of intrinsic programs that drive therapy resistance. Here we report that casein kinase-1δ (CK1δ) and CK1ε are therapeutic targets for MM that control mitochondrial metabolism. Specifically, SR-3029, a dual CK1δ/CK1ε inhibitor, has potent anti-MM activity in vivo and ex vivo (in 74/75 patient specimens). Mechanistically, RNA sequencing (RNA-seq) and metabolic analyses revealed that inhibiting CK1δ/CK1ε disables MM metabolism, by suppressing genes involved in oxidative phosphorylation (OxPhos), reducing citric acid cycle intermediates, and suppressing Complexes I and IV of the electron transport chain. Finally, sensitivity of MM patient specimens to SR-3029 correlates with elevated expression of mitochondrial genes, and RNA-seq of tumor cells from 687 MM patients spanning the spectrum from newly diagnosed to late relapsed refractory disease revealed increased CSNK1D, CSNK1E, and OxPhos genes correlate with disease progression and inferior outcomes. Thus, increases in mitochondrial metabolism are a hallmark of MM progression that can be disabled by targeting CK1δ/CK1ε.