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Heart failure (HF) is a deeply serious clinical problem that remains unsolved. Many reports highlight the cardioprotective properties of mesenchymal stem cells (MSCs), the factors contained in their secretome being particularly important for this function; these include the exosomal miRNAs (exo-miRNAs) secreted with or without stimulus which can modulate various biological processes. In search of new paradigms in heart failure, we wondered whether MSC-derived exosomal microRNAs could play a role in the management of clinical patients.To analyze whether there is sufficient evidence to support this hypothesis we designed a systematic review of studies on exo-miRNAs in heart diseases causing HF during the last decade.The cardioprotective functions of twenty-four exo-miRNAs derived from bone marrow MSCs (BM-MSCs) are known and the functions of exo-miRNAs from other MSC sources such as adipose tissue, trophoblasts, amniotic fluid, and endometrium were also determined. Inhibition of apoptosis is the most reported biological function and the targets for thirty exo-miRNAs are known.The results from this systematic review support the initial hypothesis and encourage us to test it in future experimental research works but more importantly, we seek to encourage other researchers in the field to propose other hypotheses aimed at the possible use of exo-miRNAs in HF secondary to cardiac disease.