Neurohormonal signaling and mitochondrial dynamism are seemingly distinct processes that are almost ubiquitous among multicellular organisms. Both of these processes are regulated by GTPases, and disturbances in either can provoke disease. Here, inconspicuous pathophysiological connectivity between neurohormonal signaling and mitochondrial dynamism is reviewed in the context of cardiac and neurological syndromes. For both processes, greater understanding of basic mechanisms has evoked a reversal of conventional pathophysiological concepts. Thus, neurohormonal systems induced in, and previously thought to be critical for, cardiac functioning in heart failure are now pharmaceutically interrupted as modern standard of care. And, mitochondrial abnormalities in neuropathies that were originally attributed to an imbalance between mitochondrial fusion and fission are increasingly recognized as an interruption of axonal mitochondrial transport. The data are presented in a historical context to provide insight into how scientific thought has evolved and to foster an appreciation for how seemingly different areas of investigation can converge. Finally, some theoretical notions are presented to explain how different molecular and functional defects can evoke tissue-specific disease.