Molecular signaling pathways that regulate peri-pertum cardiac remodeling are not well-understood. The objectives were to study the role of mitogen-activated protein kinases (MAPK), protein kinase B (Akt) and endothelial nitric oxide synthase (eNOS) in mediating pregnancy and post-partum (PP) cardiac remodeling. Methods: Adult female Sprague-Dawley rats were divided into non-pregnant (n=5), 18 days pregnant (n=5), 0 days post-partum (PP) (n=7), and 14 days PP (n=8). Rats underwent echocardiography under sedation to measure LV size and function and Western blots to measure myocardial protein expression of MAPKs (p38, JNK, ERK), Akt, and endothelial nitric oxide synthase (eNOS). Results: (i) During pregnancy, there was an increase in LV mass (0.62±0.03 to 1.1±0.04 g, p<0.001), mass/volume ratio (0.7±0.02 to 1.28±0.02 g/ml, p<0.0001), and ejection fraction (EF) (64±3% to 74±2%). While LV mass and mass/volume ratio returned to pre-pregnancy values in the PP period, ejection fraction remained below normal range (53±3%, p<0.05). (ii) The expression of anti-hypertrophic factors (p38, JNK, Akt) decreased during pregnancy and normalized PP except JNK that increased to higher than normal levels. eNOS also increased to higher than baseline levels PP. (iii) Activation of p38 and JNK was directly correlated with lower LV mass/volume ratio (r=-0.81 and -0.71 respectively, p<0.05). Conclusion: Pregnancy is associated with physiologic cardiac hypertrophy. There is rapid reversal of hypertrophy in the post-partum period while recovery of cardiac function is delayed possibly related to PP upregulation of JNK. A dysregulation of MAPK signaling may be an important determinant of PP cardiac dysfunction.