Dental clinicians are confronted with an increasing number of medically compromised patients who require implant surgery for their oral rehabilitation. However, there are few guidelines on dental implant therapy in this patient category, so that numerous issues regarding pre- and post-operative management remain unclear to the dental clinician. Therefore, the aim of the present review is to offer a critical evaluation of the literature and to provide the clinician with scientifically based data for implant therapy in the medically compromised patient. This review presents the current knowledge regarding the influence of the most common systemic and local diseases on the outcome of dental implant therapy, e.g., abnormalities in bone metabolism, diabetes mellitus, xerostomia, and ectodermal dysplasias. Specific pathophysiologic aspects of the above-mentioned diseases as well as their potential implications for implant success are critically appraised. In line with these implications, guidelines for pre- and post-operative management that may assist in the successful implant-supported rehabilitation of this patient category are proposed.