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The hypothesis that the large demand of reproduction negatively impacts future reproduction and/or survival has become a major topic in many fields within biology. Although many assume negative linear correlations between characteristics associated with reproduction and those supporting self-maintenance (i.e., costs of reproduction), empirical studies do not always support this assumption. In this dissertation, I investigate the factors that contribute to costs of reproduction in female house mice by using multiple approaches. The overarching goal of this dissertation is to test the assumption that the increased demands of reproduction necessarily incur costs that negatively impact self-maintenance processes, which in turn affect future reproductive performance and/or survival of mothers and their young. To achieve this goal, I used a combination of data exploration and experimental studies to assess costs of reproduction in female wild-derived and laboratory house mice. First, I explored patterns of life-history and metabolic trait co-variation at the intraspecific level across strains of inbred mice with the goal of understanding the genetic architecture that may underlie constraints to reproductive performance. I then investigated how reproductive performance changes with maternal age and protein consumption, finding that performance is not static across age and that protein intake mediates age-specific reproductive strategies without a necessary cost to future reproductive bouts. I then explored the relationship between reproduction and immune defense in my next two chapters by assessing changes in maternal antibody responses as a function of reproductive demand, as well as the developmental effects of that immune challenge on offspring. These two chapters demonstrate that methodologies used to investigate the relationship between female reproduction and immune defense should take a female-centric approach and incorporate responses in both mothers and their offspring. Together, my dissertation work contributes to the current literature by exploring gaps in our understanding and by testing implicit assumptions common among previous investigations.