Our investigations of human C-reactive protein (CRP) and CRP transgenic mice have produced novel data that firmly establish this protein as an important host defense molecule. For example, we have learned that depending on the disease model, the beneficial effect of CRP can be direct, depend on the protein's ability to engage complement and Fcγreceptors, or rely on its ability to bridge innate and adaptive immunity. In addition, the degree of protection correlates with acute phase expression, but more important, also with the amount of CRP expressed constitutively. Furthermore, differences in baseline levels of CRP among healthy individuals and among patients can be attributed to a CRP gene polymorphism. In this article, we discuss these and other observations we have made during the last 5 yr and summarize our ongoing studies and future plans related to CRP biology.