Methamphetamine (METH) is a widely abused illicit drug that is highly addictive and affects cardiac metabolism and contraction. We employed microarrays to identify mRNA differences in cardiac left ventricle (LV) gene expression following METH administration (10d, 3mg/kg/d, subcutaneously) in C57Bl/6 mice. Parallel DNA methylation changes were identified using tiled DNA microarrays to implicate epigenetic reprogramming and highlight long-term cardiac impact of METH. Gene expression arrays identified 485 genes that were differentially expressed following METH (expression fold change>1.5, p<0.05). Using pathway enrichment analysis, families relating to calcium signaling and contractility were altered in the LV by METH. With DNA methylation analysis, 10.6% of probed regions of LV DNA exhibited significant changes following METH exposure; nearly 75% of those changes were hypomethylation. By comparing gene expression and DNA methylation changes, 27 genes revealed differences by both methods of analysis. Among these, only the promoter for CACNA1C, the gene encoding L-type calcium channel Cav1.2, was hypomethylated by METH, and CACNA1C gene expression was increased by METH on microarray. For confirmation, quantitative PCR verified Cav1.2 LV mRNA increased due to METH. Correlative immunoblots revealed a 3.5-fold increase in Cav1.2 protein abundance in METH LVs compared to LVs of vehicle controls. Histopathologically, contraction band necrosis was abundant in METH LVs. These results implicate Cav1.2 in calcium dysregulation and hypercontractility in the murine LV exposed to METH and suggest possible mechanisms for METH cardiac toxicity in humans.