During protein synthesis, many proteins destined to be carried to the cell surface are tagged with a so-called signal sequence which guides their translocation into the endoplasmic reticulum. Once that job had been done, such sequences were thought to be redundant. A striking and unexpected twist comes in the form of the discovery that signal sequences have a highly specific function in immune recognition through the agency of class I molecules of the major histocompatibility complex. It turns out that they have a central place in controlling the tolerance of types of lymphocytes known as natural killer cells to the body's own tissues.