1. The fundamental tradeoff between carbon gain and water loss has long been predicted as an evolutionary driver of plant strategies across environments. Nonetheless, challenges in measuring carbon gain and water loss in ways that integrate over leaf lifetime have limited our understanding of the variation in and mechanistic bases of this tradeoff. Furthermore, the microevolution of plant traits within species versus the macroevolution of strategies among closely related species may not be same, and accordingly, the latter must be addressed using comparative phylogenetic analyses. 2. Here we introduce the concept of ‘integrated metabolic strategy’ (IMS) to describe the ratio between carbon isotope composition (δ13C) and oxygen isotope composition above source water (Δ18O) of leaf cellulose. IMS is a measure of a leaf-level conditions that integrate several mechanisms contributing to carbon gain (δ13C) and water loss (Δ18O) over leaf lifespan, with larger values reflecting higher metabolic efficiency and hence less of a trade-off. We tested how IMS evolves among closely related yet ecologically diverse milkweed species, and subsequently addressed phenotypic plasticity in response to water availability in species with divergent IMS. 3. IMS varied strongly among 20 Asclepias species when grown under controlled conditions, and phylogenetic analyses demonstrate species-specific tradeoffs between carbon gain and water loss. Larger IMS values were associated with species from dry habitats, with larger carboxylation capacity, smaller stomatal conductance and smaller leaves; smaller IMS was associated with wet habitats, smaller carboxylation capacity, larger stomatal conductance and larger leaves. The evolution of IMS was dominated by changes in species’ demand for carbon (δ13C) more so than water conservation (Δ18O). Although some individual physiological traits showed phylogenetic signal, IMS did not. 4. In response to experimental decreases in soil moisture, three species maintained similar IMS across levels of water availability because of proportional increases in δ13C and Δ18O (or little change in either), while one species increased IMS due to disproportional changes in δ13C relative to Δ18O. 5. Synthesis: IMS is a broadly applicable mechanistic tool; IMS variation among and within species may shed light on unresolved questions relating to evolution and ecology of plant ecophysiological strategies.