In recent years, a wealth of studies have identified various molecular species released by cardiac muscle under physiological and pathological conditions which exert local paracrine and/or remote endocrine effects. Conversely, humoral factors, principally produced by organs such as skeletal muscle, kidney or adipose tissue, may affect the function and metabolism of normal and diseased hearts. While this cross-communication within cardiac tissue and between the heart and other organs is supported by mounting evidence, research on the role of molecular mediators carried by exosomes, microvesicles and apoptotic bodies, collectively defined as extracellular vesicles (EVs), is at an early stage of investigation. Once released in the circulation, EVs can potentially reach any organ where they transfer their cargo of proteins, lipids and nucleic acids which exert potent biological effects on recipient cells. While there are a few cases where such signaling was clearly demonstrated, the results from many others studies can only be tentatively inferred based on indirect evidence obtained by infusing exogenous EVs in experimental animals or by adding them to cell cultures. This area of research is in rapid expansion and most mechanistic interpretations may change in the near future, hence the present review on the role played by EV-carried mediators in the two-way communication between heart and skeletal muscle, kidneys, bone marrow, lungs, liver, adipose tissue and brain is necessarily limited. Nonetheless, the available data are already unveiling new, intriguing and ample scenarios in cardiac physiology and pathophysiology.