Maternal physiology changes dramatically during the course of gestation and lactation to meet the needs of the developing fetus and newborn. In the present study, we examined the influence of pregnancy and lactation on growth and erythroid gene expression patterns of the maternal spleen. Holtzman Sprague-Dawley rats and CD-1 mice were killed at various stages of gestation and post partum. We observed pregnancy dependent increases in spleen weight and spleen DNA content in both the rat and mouse. In the rat, spleen size was greatest at the end of pregnancy and regressed post partum. In contrast, mouse spleen size peaked by gestational Day 13 and regressed to its non-pregnant weight before parturition. Pregnancy dependent changes in the size of the spleen were primarily due to an increase in red pulp. Maternal spleen expression of erythroid-associated genes (erythroid Krüppel-like factor, erythroid 5-aminolevulinate synthase-2, β-major globin) was influenced by pregnancy and lactation. A pregnancy dependent increase in erythroid progenitors was also observed. In summary, the demands of pregnancy and lactation cause marked adaptations in the maternal spleen. The maternal spleen increases in size and exhibits an expansion of the erythroid lineage.