A previous analysis of covalent modification systems (Goldbeter, A., and Koshland, D. E., Jr. (1981) Proc. Natl. Acad. Sci. U. S. A. 78, 6840-6844) showed that steep transitions in the amount of modified protein can occur when the converter enzymes are saturated by their protein substrate. This "zero-order ultrasensitivity" can further be amplified when an effector acts at more than one step in a monocyclic or multicyclic cascade of covalent modification. We analyze the limitations of the latter "multistep ultrasensitivity" and show how it can combine with the zero-order effect to enhance the sensitivity of biochemical systems controlled by covalent modification.