Gene transcript changes after exposure to the heart toxin, bis(2-chloroethoxy)methane (CEM), were analyzed to elucidate mechanisms in cardiotoxicity and recovery. CEM was administered to 5-week-old male F344/N rats at 0, 200, 400, or 600 mg/kg by dermal exposure, 5 days per week, for a total of 12 doses by study day 16. Heart toxicity occurred after 2 days of dosing in all 3 regions of the heart (atrium, ventricle, interventricular septum) and was characterized by myofiber vacuolation, necrosis, mononuclear-cell infiltration, and atrial thrombosis. Ultrastructural analysis revealed that the primary site of damage was the mitochondrion. By day 5, even though dosing was continued, the toxic lesions in the heart began to resolve, and by study day 16, the heart appeared histologically normal. RNA was extracted from whole hearts after 2 or 5 days of CEM dosing. After a screen for transcript change by microarray analysis, dose-response trends for selected transcripts were analyzed by qRT-PCR. The selected transcripts code for proteins involved in energy production, control of calcium levels, and maintenance of heart function. The down-regulation of ATP subunit transcripts (Atp5j, ATP5k), which reside in the mitochondrial membranes, indicated a decrease in energy supply at day 2 and day 5. This was accompanied by down-regulation of transcripts involved in high-energy consumption processes such as membrane transport and ion channel transcripts (e.g., abc1a, kcnj12). The up-regulation of transcripts encoding for temperature regulation and calcium binding proteins (ucp1 and calb3) only at the 2 low exposure levels, suggest that these adaptive processes cannot occur in association with severe cardiotoxicity as seen in hearts at the high exposure level. Transcript expression changes occurred within 2 days of CEM exposure, and were dose-and time-dependent. The heart transcript changes suggest that CEM cardiotoxicity activates protective processes associated energy conservation and maintenance of heart function.