A growing body of evidence shows that lactation is energetically costly for mammals. Although lactation costs are positively correlated with litter size, the shape of this relationship remains largely unexplored. Understanding physiological efficiencies of metabolic investment in reproduction should provide valuable insight concerning trade-offs between number and size of offspring and limits to litter size. I used data from northern grasshopper mice (Onychomys leucogaster) to explore these constraints. The relationship between litter size and cost of lactation was best described by a non-linear regression such that intermediate litter sizes were the most cost-effective. Lactation costs at the upper range of natural litters for this species required mothers to ingest more than twice as much food as non-reproductive females. Young at 15 d of age from the largest litters were smaller than same-age young from smaller litters. In contrast, young from litters at the lower end of the species range were larger than average. These data suggest that the distribution of litter sizes within this species is selected against at the lower end by inefficient conversion of energy into viable offspring and at the upper end by simple limits on digestive efficiency or capacity.