Direct skeletal fixation, termed osseointegration, has expanded in the last century and includes use in total joint replacements, the edentulous mandible and maxilla, and percutaneous osseointegrated prosthetics. Although it is well known that titanium and bone have the ability to form a durable bone–implant interface, new applications have emerged in the field of orthopedics, which requires a more thorough assessment of the literature. This review aims to introduce the basic biological principles for attaining osseointegration and discusses the major factors for assuring successful cementless fixation.