Heart failure is a consequence of an injured or diseased heart undergoing pathological remodeling to match cardiac output with the metabolic needs of the body. 8 million people are confirmed with heart failure in Europe and the USA combined. With few exceptions the prognostic benefits of current treatments are limited, resulting in high rates of morbidity and mortality. Regulatory pathways involved in cardiac development may have utility in reprogramming cardiomycytes to aid in cardiac repair. As an alternative to stem cell therapy we hypothesize that small, secreted peptides or their derivatives together with other small molecules such as microRNAs are alternatives for tissue repair stimulation. These molecules are believed to modulate the activation of resident cardiac stem/progenitor cell populations. A systematic approach to understanding the signaling mechanisms actuated by such proteins will benefit the design of novel therapeutic agents to promote cardiac repair and regeneration in adults and children.