Genome size has long been hypothesized to affect the metabolic rate in various groups of animals. The mechanism behind this proposed association is the nucleotypic effect, in which large nucleus and cell sizes influence cellular metabolism through surface area-to-volume ratios. Here, we provide a review of the recent literature on the relationship between genome size and metabolic rate. We also conduct an analysis using phylogenetic comparative methods and a large sample of extant vertebrates. We find no evidence that the effect of genome size improves upon models in explaining metabolic rate variation. Not surprisingly, our results show a strong positive relationship between metabolic rate and body mass, as well as a substantial difference in metabolic rate between endothermic and ectothermic vertebrates, controlling for body mass. The presence of endothermy can also explain elevated rate shifts in metabolic rate whereas genome size cannot. We further find no evidence for a punctuated model of evolution for metabolic rate. Our results do not rule out the possibility that genome size affects cellular physiology in some tissues, but they are consistent with previous research suggesting little support for a direct functional connection between genome size and basal metabolic rate in extant vertebrates.