A recent paper by Nisoli et al.1 provides the first evidence that elevated levels of nitric oxide (NO) stimulate mitochondrial biogenesis in a number of cell lines via a soluble guanylate-cyclase-dependent signaling pathway that activates PGC1α (peroxisome proliferator-activated receptor γ coactivator-1α), a master regulator of mitochondrial content. These results raise intriguing possibilities for a role of NO in modulating mitochondrial content in response to physiological stimuli such as exercise or cold exposure. However, whether this signaling cascade represents a widespread mechanism by which mammalian tissues regulate mitochondrial content, and how it might integrate with other pathways that control PGC1α expression, remain unclear. BioEssays 25:538–541, 2003. © 2003 Wiley Periodicals, Inc.