Both phenotypic plasticity and genotypic specialization can contribute to differences in physiological performance in species that are locally adapted to different environments. However, their relative contributions are expected to vary with respect to the spatial and temporal grain of environmental variation. In species that are distributed across steep elevational gradients, environmental conditions change dramatically over small spatial scales, and as a result, adaptive variation in physiological performance may be attributable to transcriptional plasticity in regulatory networks that underlie trait differences between high- and low-elevation populations. In this talk, I will discuss a series of common-garden experiments that were designed to examine the role of regulatory plasticity in evolutionary adaptation to high-elevation conditions in deer mice (Peromyscus maniculatus), the species with broadest elevational distribution of any North American mammal. Using a system-biology framework, I will discuss our efforts to integrate genomic surveys of DNA sequence polymorphism and genome-wide transcriptional profiles with functional assays of metabolic enzyme activities, cellular and tissue-level phenotypes, and measures of whole-animal performance. Highland mice exhibit greater thermogenic capacities than lowland mice under hypoxia, and this trait is associated with increased survival at high elevation. Our recent work has shown that this enhanced performance is associated with upregulation of transcriptional modules that influence several hierarchical steps in the O2 transport cascade, including tissue O2 diffusion (angiogenesis) and tissue O2 utilization (muscle fiber composition, metabolic fuel use, and cellular oxidative capacity). Most of these performance-related transcriptomic and physiological changes occur over physiological and developmental timescales, suggesting that regulatory plasticity makes important contributions to fitness-related physiological performance in highland deer mice.