As a biologic product derived from human tissue, acellular dermal matrices did not require premarket approval for their initial use as a soft-tissue support product. Since their first use in breast surgery, acellular dermal matrices have allowed for numerous advances in breast reconstruction. They quickly gained popularity in breast surgery and are used frequently in various applications. During an investigation into potential factors leading to breast implant-associated anaplastic large-cell lymphoma, the U.S. Food and Drug Administration made an official statement that acellular dermal matrices were not approved for use in breast reconstruction and that using them in breast surgery was considered off-label. This special topic article details the history of acellular dermal matrices in breast surgery and describes the ongoing evolution of the relationship between the U.S. Food and Drug Administration and acellular dermal matrices.