Many protein kinases are activated strongly by the phosphorylation of a polypeptide region (activation loop) that lies outside the active-site cleft. Analysis of the X-ray crystallographic structures of the insulin receptor with the activation loop in the phosphorylated and dephosphorylated forms offers a testable model for the mechanism of activity regulation by the loop. In this model, the dephosphorylated activation loop can act as an autoinhibitor by blocking substrate access to the active site. Phosphorylation of the loop could then release the autoinhibitor from the active site, allowing substrate binding and catalysis. While this model has been widely invoked, it was not clear if solution studies would support an autoinhibitory model for kinase regulation, in general. We review the results of solution studies on six protein kinases that test the role of the activation loop in controlling active-site access. While loop phosphorylation enhances substrate binding in two cases, four protein kinases display little or no effect on substrate dissociation constants. By comparison, phosphorylation increases catalysis by 2-4 orders of magnitude in all cases. These findings can be used to place the phosphorylatable activation loops into two broad, functional subcategories. (i) Gated activation loops exhibit bifunctional properties restricting substrate access and controlling catalysis. (ii) Nongated activation loops allow free movement of the substrate in and out of the active site irrespective of phosphorylation state but potently modulate the phosphoryl transfer step. Thus, while activation loop phosphorylation greatly modulates catalytic potential, it does not necessarily affect substrate binding, as once widely believed.