Mitochondrial architecture is involved in several functions crucial for cell viability, proliferation, senescence, and signaling. In particular, mitochondrial dynamics, through the balance between fusion and fission events, represents a central mechanism for bioenergetic adaptation to metabolic needs of the cell. As key regulators of mitochondrial dynamics, the fusogenic mitofusins have recently been linked to mitochondrial biogenesis and respiratory functions, impacting on cell fate and organism homeostasis. Here we review the implication of mitofusins in the regulation of mitochondrial metabolism, and their consequence on energy homeostasis at the cellular and physiological level, highlighting their crucial role in metabolic disorders, cancer, and aging.