My laboratory is applying contemporary techniques of biochemistry and molecular biology to an important emerging field in biomedicine: the evolution of the immune system. Our investigations will build upon the discoveries that key immunoregulatory molecules (i.e., cytokines), that function in the mammalian immune response appear to be present in phylogenetically distinct invertebrate species. Herein, we propose the term macrokine to describe invertebrate proteins that have vertebrate cytokine-like activities. The wide distribution of such basic elements of innate host defense responses demonstrates its antiquity in animal evolution. Through these studies we hope to identify the more ancient facets of the vertebrate innate immune response. In turn, these observations may help clarify host defense functions and responses not yet appreciated in the vertebrate immune system.