Over a 30-year period, a range of directed exchange methods have been developed to label target molecules with isotopic hydrogen. Among these methods, those involving ortho-direction have proved particularly useful for labelling a wide selection of drugs, drug candidates, agrochemicals, biochemicals, natural products and other significant agents with both tritium and deuterium. The approach has involved the identification of new catalysts for ortho-directed exchange including RhCl 3 Á 3H 2 O for the one-step labelling of carboxylic acids, amides, anilides, etc., with deuterium at high abundance, and with tritium at low and high specific activities from an isotopic water donor; CODIr(CH 3 Á CO Á CH 2 Á CO Á CH 3 ), a similar and often more active catalyst with a somewhat different spectrum of directing substituents; CODIr(CF 3 Á CO Á CH 2 Á CO Á CF 3 ), a catalyst for the labelling of benzylamines, anilines and heterocyclics utilizing isotopic hydrogen gas as the donor, and which is active even in dipolar aprotic solvents; and latterly, solid-phase iridium(1)-based catalysts, with activities similar to the Heys and Crabtree catalysts, which have significant advantages over their homogenous counterparts in tritium-labelling via the ortho-direction approach.