Guided tissue regeneration (GTR) affords the clinician the ability to successfully manage a variety of severe periodontal problems, without engendering the prosthetic commitment necessary for the use of root resective techniques. However, such therapy is highly diagnostic- and technique-sensitive. This article provides a clinical basis for using GTR and maximizing therapeutic outcomes, and discusses the challenges posed by deep infrabony defects and furcation involvements. The discussion also focuses on the need for GTR therapy to treat such lesions comprehensively.