The metabolic syndrome (MetS) is a constellation of multiple metabolic risk factors including obesity, glucose intolerance, insulin resistance, dyslipidemia and hypertension. Individuals with MetS are found to be afflicted with an increased risk of type 2 diabetes mellitus and overall cardiovascular diseases. One of the common comorbidities of MetS is the impairment of heart function en route to loss of cardiomyocytes and ultimately heart failure. Although it is accepted that cardiomyocytes are terminally differentiated, recent evidence has challenged this concept to indicate the ability of cardiomyocytes to regenerate from progenitor cells of the heart and other organs. Moreover, it has been suggested that pathological conditions such as MetS may play a role in the regulation of cardiomyocyte regeneration. This mini-review will discuss the role of MetS in the regulatory machineries of cardiomyocyte regeneration.