A review. Although the synthesis of beta -lactams by means of tethered Ugi reactions was known since the early 1960s, the 1995 report from Ugi's group could be regarded as a turning point in the development of novel multicomponent reactions (MCRs) for heterocycle syntheses. Indeed, the no. of articles describing isocyanide-based multicomponent syntheses of heterocycles has increased steadily since then. Although most of these novel MCRs still exploit the archetypal reactivity of isocyanide, its pronounced ability to undergo alpha -addn. with electrophiles (sp2- and sp-carbon atoms) and nucleophiles, new MCRs have also been discovered as a consequence of exploiting the different secondary reactions of this alpha -adduct. Since most of these MCRs were devised on the basis of known bimol. reactions, judicious combination of reactive functional groups within substrates is of fundamental importance. While the combinatorial principle can help in finding and exploring new MCRs, we would advocate a "substrate-design approach" in searching for novel MCRs. [on SciFinder (R)]