The link between chronic oral infections and general health has been recognized since the early 20th century. During the last 2 decades, retrospective epidemiological studies and prospective longitudinal, as well as intervention, studies have supported that these chronic oral infections with accompanying chronic inflammation associate with various systemic diseases and their sequelae. This continuation application for the Center for the Biologic Basis of Oral/System Diseases (CBBO/SD) addresses major initiatives of the National Institute of Dental and Craniofacial Research (NIDCR) regarding improving oral and general health of the U.S. population. The CBBO/SD is organized into 3 clinical projects: Project 1: Chronic Inflammation at the Oral and Cervico/Vaginal Mucosa; Project 3: Coordinated Oral-Intestinal Immune Response in Patients with Inflammatory Bowel Diseases; and 2 translational science projects: Project 4: Ontogeny of Innate Immune Responses at Mucosal Surfaces; and Project 5: Gene Therapy for Orofacial Pain. These projects enlist junior investigators from the Colleges of Dentistry, Nursing, and Medicine, as well as senior mentors/co-investigators from multiple colleges at UK. The thematic interface of the projects focuses on the contribution of chronic inflammation to oral and systemic diseases. They engage populations of expectant women, patients with chronic orofacial pain, and inflammatory bowel disease. These clinical projects interact with the translational projects at the level of a common understanding of innate immune responses and inflammation, and novel therapeutic intervention strategies for the chronic orofacial pain. The CBBO/SD provides an infrastructure for development of the junior faculty by providing grants management support, educational opportunities, a biostatistics/bioinformatics core, and a clinical research center. The continuation of the CBBO/SD is supported by the success during the initial tenure of the center in transitioning junior investigators towards independent funding, coupled with substantial investment from the university and individual colleges.