A number of 4-X-bioimidazoles are accessible by direct electrophilic substitution (nitro, halo, etc.); 2-X-bioimidazoles are far less accessible and can be obtained ,only by indirect and, often, very tortuous routes. Prior to our major efforts in this area, the majority of 2-X-bioimidazoles were unknown. By far the 2-substituted imidazoles most easily obtainable are 2-iodo and 2-(trifluoromethyl). The 2-iodo derivatives of histidine and histamine are of interest, not only because of their potent antimalarial activities, but because they can serve as valuable intermediates for the synthesis of other 2-X-bioimidazoles, as can the trifluoromethyl analogues. 'We are currently exploring the utility of such conversions to prepare photosensitive bioimidazoles and affinity labels for in vivo use. Over the past 15 years, we have found consistently that 2-X-bioimidazoles (especially fluoro and iodo) have a broad range of strong biological activities but ,the corresponding 4-X-bioimidazoles are essentially inactive. Various explanations for this remarkable selectivity in biorecognition have been invalidated on experimental grounds. Our analyses of (13)C NMR spectra have now revealed that the differentiation may be based solely on tautomer preference. While 4-X-imidazoles exist preferentially as the unnatural pi-tautomers, 2-X-bioimidazoles exist preferentially natural tau-tautomers. This discovery generates broad implications in many areas of drug design, e.g., selective antihistamines, imidazole-based antimalarials and antimicrobials, CVS and CNS-selective TRH analogues, and analogues based on pyrrole and triazole regioisomerism. Thus. novel synthetic methods are being explored to make available even more 2-X-bioimidazoles.