In mammals, the peroxisome proliferator activated receptor (PPAR)gamma coactivator-1alpha (PGC-1alpha) is a central regulator of mitochondrial gene expression, acting in concert with nuclear respiratory factor-1 (NRF-1) and the PPARs. Its role as a "master regulator" of oxidative capacity is clear in mammals, but its role in other vertebrates is ambiguous. In lower vertebrates, although PGC-1alpha seems to play a role in coordinating the PPARalpha axis as in mammals, it does not appear to be involved in NRF-1 regulation of mitochondrial content. To evaluate the evolutionary patterns of this coactivator in fish and mammals, we investigated the evolutionary trajectories of PGC-1alpha homologs in representative vertebrate lineages. A phylogeny of the PGC-1 paralogs suggested that the family diversified through repeated genome duplication events early in vertebrate evolution. Bayesian and maximum likelihood phylogenetic reconstructions of PGC-1alpha in representative vertebrate species revealed divergent evolutionary dynamics across the different functional domains of the protein. Specifically, PGC-1alpha exhibited strong conservation of the activation/PPAR interaction domain across vertebrates, whereas the NRF-1 and MEF2c interaction domains experienced accelerated rates of evolution in actinopterygian (fish lineages) compared to sarcopterygians (tetrapod lineages). Furthermore, analysis of the amino acid sequence of these variable domains revealed successive serine- and glutamine-rich insertions within the teleost lineages, with important ramifications for PGC-1alpha function in these lineages. Collectively, these results suggest modular evolution of the PGC-1alpha protein in vertebrates that could allow for lineage-specific divergences in the coactivating capabilities of this regulator.