The protein serine/threonine phosphatases constitute a unique class of enzymes that are critical regulatory enzymes as they must counteract the activities of thousands of protein kinases in human cells. Uncontrolled inhibition of phosphatase activity by toxic inhibitors can lead to widespread catastrophic effects. Over the past decade, a number of natural product toxins have been identified which specifically and potently inhibit protein phosphatase-1 and -2A. Among these are the cyanobacteria-derived cyclic heptapeptide microcystin-LR and the polyether fatty acid okadaic acid from dinoflagellate sources. The molecular mechanism of the potent inhibition of protein phosphatase-1 by these toxins is becoming clear through insights gathered from diverse sources. These include: 1. Comparison of structural variants of the toxins, 2. Delineating the structural differences between protein phosphatase-1 and -2A accounting for their differing sensitivity to okadaic acid, 3. Determination of the crystal structure of protein phosphatase-1 with microcystin-LR bound and, most recently, 4. Mutagenesis of protein phosphatase-1. Taken together, these data point to a common binding site on protein phosphatase-1 for okadaic acid and microcystin-LR. However, the details of these data suggest that each toxin binds to the common site in a subtly different way, relying on common structural interactions to different degrees. Finally, the insights derived from protein phosphatase-1 may help explain different sensitivities of other protein serine/threonine phosphatases to toxin inhibition due to the high degree of structural conservation among many members of this enzyme family.