Immunity mechanisms have existed since early life forms arose around 3700 million years ago (MYA) but the sophistication and complexity of reactions towards invasive molecules and organisms has increased immensely since. The Cambrian explosion around 500 MYA was associated with a rich expansion of life forms and species and with this event appeared a plethora of immune gene and protein variations. In general, the main pillars of immunity cover (1) recognition of self/non-self; (2) immunological memory; (3) cell-to-cell signaling; (4) humoral effector mechanisms; and (5) cellular effector mechanisms. The cellular arm of immunity is a basic requirement present in early amoebae that allowed them to demonstrate phagocytosis and extracellular trapping of pathogens. Unicellular organisms, such as ciliates, are also able to differentiate self from non-self. Immunological memory, involving cellular and humoral factors, can be traced in invertebrates, such as snails, providing the host organism with lasting protection against invading pathogens. Innate immunological reactions comprising both cellular and humoral factors have in this way proven protective for invertebrates, but with the advent of vertebrates the adaptive branch of immunity became highly developed, involving variable lymphocyte receptors and major histocompatibility complex (MHC). Teleost fishes display in principle a well-developed immune system dependent on myeloid and lymphoid cell lines, immunological memory, immunoglobulin production, MHC, and antigen presentation. Signal molecules orchestrating complex immune reactions can be traced in rather early invertebrates, but the richness and diversity of cytokine families appeared with fishes. The adaptive features have a close connection with the innate immune mechanisms that have in modern times developed into the armament protecting amphibians, reptiles, birds, and mammals from adverse molecules and pathogens.