As the climate crisis continues to alter temperature regimes and water availability, studying how animals regulate water balance grows in importance. We studied variation in water loss across the skin among body regions and its plasticity in response to humidity acclimation in Western Fence Lizards (Sceloporus occidentalis). We examined the effects of climatic and physiological variables on cutaneous evaporative water loss (CEWL) and compared CEWL rates among body regions (dorsum, ventrum, head, dewlap, and mite patch). The best model to explain baseline variation in log-transformed CEWL included: body region; lizard mass; ambient temperature, vapor pressure deficit (VPD), and solar radiation at the time of capture; body temperature, ambient temperature, and VPD at the time of CEWL measurement; and the interactions between body region and each of mass and VPD at the time of capture. These results demonstrate cutaneous osmoregulatory variability among lizards based on climate and body size and within individual lizards based on body region. We also tested CEWL plasticity in response to humidity acclimation. Lizards exposed to humid conditions for 8 d exhibited increased CEWL, and lizards exposed to dry conditions exhibited decreased CEWL compared to initial measurements. This is evidence for rapid and significant acclimatory responses of CEWL in response to changes in environmental humidity. Such variation and plasticity suggest that lizards possess a certain degree of ability for using osmoregulatory changes to respond to climate change.