MicroRNAs (miRs) are most often depicted as fine-tuners of gene expression, and more occasionally as genetic switches. Still few examples delineate their contributions as phenotypic modulators. We reasoned that browsing their contribution to genetic disease could provide a framework for understanding some of the requirements to devise miRNA-based therapy strategies. Here we will browse through what appeared as a mitochondrial view of miRs. We will provide examples showing that miRs may be crucial in the regulation of mitochondrial components, such as in the case of Friedreich ataxia. Conversely, we will present the rationale that supports their involvement within the mitochondrion.