Most heart conditions leading to sudden death or impaired heart pumping functions in the young people (< 35 years old) are the results of genetic mutations inherited from parents. It is very difficult to find curative therapy for these inherited heart diseases due to late diagnosis and lack of understanding in how genetic mutations cause heart dysfunction. One of these inherited heart diseases is named arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). The signature features of sick ARVD/C hearts are progressive heart muscle loss and their replacement by fat and scar tissues, which can lead to lethal irregular heart rhythms or heart failure. We made significant breakthrough and successfully modeled sick ARVD/C heart muscles in cell cultures using versatile stem cells derived from ARVD/C patients’ skin cells with genetic mutations in desmosomal proteins (a specific type of cell-cell junctions in hearts), e.g. plakophilin-2 (Pkp2), desmoplakin (Dsp), etc. Using heart cells derived from ARVD/C-specific stem cells, we discover specific abnormalities in energy consumption of ARVD/C heart muscles that lead to their dysfunction and death. We have generated and characterized additional stem cells lines from ARVD/C patients with different desmosomal mutations from Pkp2 mutations. We confirmed that the same metabolic deregulation occurred in heart muscles derived from new ARVD/C patient-specific stem cells with different mutations from Pkp2. Most importantly, we have cracked the disease codes and elucidated the entire key pathogenic networks underlying how mutations in Pkp2 lead to metabolic derangement in ARVD/C heart cells. Based on these novel findings, we identified and tested two potential clinically safe drugs in their efficacy of treating an established ARVD/C mouse model. We found that these two drugs are effective in reducing deterioration of cardiac function in ARVD/C mice, which will be the foundation for future clinical therapeutic testing in human patients with ARVD/C. This is the first time that a patient-specific stem cell based in-vitro model leads to novel pathogenic insights and to permit the development of novel ARVD/C-specific therapies in vivo.