Total colonic aganglionosis is a relatively uncommon form of Hirschsprung's disease (HSCR). It occurs in approximately 2-13 % of HSCR cases and involves the entire colon which is aganglionic but may extend proximally into varying lengths of small bowel. As a result, it should be separated into Total colonic aganglionosis (TCA) [defined as aganglionosis extending from the anus to at least the ileocaecal valve but no more than 50 cm small bowel proximal to the ileocaecal valve] and total colonic and small bowel aganglionosis (TCSA) which may involve very long segments of small bowel aganglionosis. Clinically, TCA appears to represent a different spectrum of disease in terms of presentation and difficulties which may be experienced in diagnosis suggesting a different pathophysiology from the more common forms of HSCR. It is therefore not yet clear whether TCA merely represents a long form of HSCR or a different expression of the disease. A number of differences exist between TCA and other forms of HSCR which require explanation if its ubiquitous clinical features are to be understood. In addition to the usual explanations for the aganglionosis of HSCR, there is some evidence suggesting that in place of being purely congenital, it may represent certain different pathophysiologic mechanisms, some of which may continue to be active after birth. This study reviews what is known about the clinical, radiological and histopathologic differences between TCA and the more frequently encountered recto-sigmoid (or short-segment; S-HSCR) and correlates them with what is currently known about the genetic and molecular biologic background to find possible pathogenetic mechanisms.