The human mitochondrial transcriptome, although produced from a small and compact genome, has revealed surprising complexity in its composition and regulation. Wide variation between individual tRNAs, mRNAs, and rRNAs indicate the importance of post-transcriptional processing, maturation, and degradation mechanisms in the regulation of mitochondrial gene expression. RNA-binding proteins play essential roles in controlling the mitochondrial transcriptome from its synthesis to its destruction and have evolved unique features to complement the unusual features of mitochondrial RNAs. Recent studies have shown how changes in mitochondrial RNAs and their binding proteins can have significant effects on human health. This opens new avenues for investigation of mitochondrial RNA-binding proteins and the mechanisms by which they regulate mitochondrial gene expression.