The human oral cavity contains a large number of different microbial habitats. When microbes from the oral indigenous flora colonize the interspace between the tooth and the connective tissue, they induce an inflammatory response. If the microbes are in sufficient numbers, and release components that cause an imbalance in the host inflammatory response, degenerative processes in the surrounding tissues are induced, ultimately resulting in periodontal disease. The disease progress depends on bacterial load, the composition of the microbial community, and host genetic factors. The two most studied periodontal pathogens, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans express virulence factors, including proteases and exotoxins. Periodontal infections are also linked to the risk pattern of several systemic diseases. We would like to shed light on the mechanisms behind periodontitis and the associations of periodontal infections with systemic inflammation. Seven articles are included in this Special Issue and cover several pathogenic processes in the periodontal infection with capacity to cause imbalance in the host response. Highlights from each of the published papers are summarized and discussed below.