Protein serine/threonine phosphatases control key biological pathways including early embryonic development, cell proliferation, cell death, circadian rhythm and cancer. Recent studies have provided important insights into how several of the many phosphatase regulators, through their interaction with a conserved phosphatase catalytic subunit, control the activity of critical substrates in these diverse pathways. Recent co-crystal structures provided a major insight into how the diverse protein serine/threonine regulators rein in the otherwise promiscuous catalytic subunits.