Memory was traditionally considered an exclusive hallmark of adaptive immunity. This dogma was challenged by recent reports that myeloid cells can retain ‘memory’ of earlier challenges, enabling them to respond strongly to a secondary stimulus. This process, designated ‘trained immunity’ is initiated by modulation of precursors of myeloid cells in the bone marrow. The ancestral innate immune system of lower organisms (e.g., Caenorhabditis elegans) can build long-lasting memory that modifies responses to secondary pathogen encounters. We posit that changes in cellular metabolism may be a common denominator of innate immune memory from lower animals to mammals. We discuss evidence from C. elegans and murine/human systems supporting the concept of an ancestral principle regulating innate immune memory by controlling cellular metabolism.