Aims: The sphingosine kinase (SphK)/sphingosine 1-phosphate (S1P) pathway, known to determine the fate and growth of various cell types, can enhance cardiac myocyte (CM) survival in vitro and provide cardioprotection in acute ex vivo heart preparations. However, the relevance of these findings to chronic cardiac pathology has never been demonstrated. We hypothesized that S1P signaling is impaired during chronic remodeling of the uninfarcted ventricle during the evolution of post-myocardial infarction (MI) cardiomyopathy, and that therapeutic enhancement of S1P signaling would ameliorate ventricular dysfunction. Methods: SphK expression and activity were measured in the remote, uninfarcted myocardium (RM) of C57Bl/6 mice subjected to coronary artery ligation. mRNA expression of S1P receptor isoforms was also measured, as was activation of downstream S1P receptor mediators. A cardioprotective role for S1P₁ receptor agonism was tested via administration of the S1P₁-selective agonist SEW2871 during and after MI. Results: Expression data suggested that a dramatic reduction in SphK activity in the RM early after MI may reflect a combination of post-transcriptional and post-translational modulation. SphK activity continued to decline gradually during chronic post-MI remodeling, when S1P₁ receptor mRNA also fell below baseline. S1P1-specific agonism with oral SEW 2871 during the first two-weeks after MI reduced apoptosis in the RM and resulted in improved myocardial function as reflected in echocardiographic measurement of fractional shortening. Conclusion: These results provide the first documentation of alterations in S1P-mediated signaling during the in situ development of cardiomyopathy, and suggest a possible therapeutic role for pharmacologic S1P receptor agonism in the post-MI heart.