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Mitochondria are crucial for many cellular functions. In this issue of Cell Reports, studies from Lanning et al. and Wolf and Mootha describe RNAi approaches to screening the mitochondrial proteome. Unexpectedly, they uncover key roles for two poorly characterized mitochondrial proteins: AK4 and FASTKD4. These studies provide examples of the power of forward genetic screens, even when screening a subset of genes, in deciphering functions of previously mysterious mitochondrial proteins.