The PII proteins are one of the most widely distributed families of signal transduction proteins in nature. They are pivotal players in the control of nitrogen metabolism in bacteria and archaea, and are also found in the plastids of plants. Quite remarkably, PII proteins control the activities of a diverse range of enzymes, transcription factors and membrane transport proteins, and in recent years the extent of these interactions has been recognized to be much greater than heretofore described. Major advances have been made in structural studies of PII proteins, including the solution of the first structures of PII proteins complexed with their targets. We have also begun to gain insights into how the key effector molecules, 2-oxoglutarate and ATP/ADP, influence the activities of PII proteins. In this review, we have set out to summarize our current understanding of PII biology and to consider where future studies of these extraordinarily adaptable proteins might lead us.