This review focuses on the effects of various cardiovascular risk factors (diabetes, aging, obesity, smoking, alcohol, depression, gender, comedications) on cardiac STAT3, a well-known cardioprotective signal molecule, under non-ischaemic baseline conditions and in settings of ischaemia/reperfusion injury with or without cardioprotective strategies. The gene discussed is STAT3; the disease is obesity due to melanocortin 4 receptor deficiency.