Appropriate control of leukocyte recruitment and activation is a fundamental requirement for competent host defense and resolving inflammation. A pivotal event that defines the successful outcome of any inflammatory event is the transition from innate to acquired immunity. In IL-6 deficiency, this process appears defective, and a series of in vivo studies have documented important roles for IL-6 in both the resolution of innate immunity and the development of acquired immune responses. Within this review, particular attention will be given to the regulatory properties of the soluble IL-6 receptor and how its activity may affect chronic disease progression.