Substrates that are specific for the "hydrolytic" activities of AdoHcy hydrolase have been recently identified. Upon interaction with the AdoHcy hydrolase such substrates generate the "active" electrophiles which then react with the enzyme nucleophiles to produce covalent inhibition. Dihalohomovinyl and haloacetylene analogues derived from adenosine as well 5'-S-allenyl-5'--thioadenosine derivative have been characterized as the first type II mechanism-based inhibitors of AdoHcy hydrolase that rely only on the "hydrolytic" activity. Design and synthesis of the novel adenine nucleosides as well their interaction with AdoHcy hydrolase are discussed in this review.