The size and organization of the animal mitochondrial genome has been reduced and compacted significantly since its endosymbiosis from an α-proteobacterial ancestor. This compaction has necessitated the evolution of unique mechanisms to facilitate rapid changes in gene expression in response to the changing energy demands of the cell. The mitochondrial transcriptome encodes proteins that are subunits of the respiratory chain, responsible for most of the energy production required by the cell. Consequently the coordinated regulation of the mitochondrial transcriptome by the nucleus is of particular importance for the maintenance of cell health and energy metabolism. Over the last few years we have investigated the unusual features of mitochondrial RNAs and the RNA-binding proteins that control their production, maturation, translation and stabilization to understand the regulation of mitochondrial gene expression and its contribution to health and disease. We have characterised several important classes of sequence specific RNA-binding proteins in cells and mouse models of disease. We have established new tools and methods for massively parallel sequencing and analyses of RNase-accessible regions of mitochondrial RNAs to investigate the functions of these proteins in a high throughput manner in vivo. To date the regulation of mitochondrial RNA metabolism and its importance for ribosome biogenesis and energy metabolism are not clear. I will discuss the in vivo role of mitochondrial RNA regulation and its importance for mitochondrial biogenesis and energy metabolism.