Multicomponent reactions (MCRs) are versatile syntheses for obtaining structurally diverse sets of complex scaffolds with high efficiency. As such, they can be attractive synthetic tools for the realization of diversity- and/or biology-oriented synthesis design strategies for focused libraries. In this account, we present an overview of our contribution to the design of novel MCRs to access a high level of molecular complexity and diversity. In addition, we demonstrate our biocatalysis/MCR sequences to obtain stereoenriched product scaffolds. 1 Introduction 2 The Build/Couple/Pair Strategy 3 Rational Design of Multicomponent Reactions 3.1 Single Reactant Replacement 3.2 Modular Reaction Sequences 3.3 Conditions-Based Divergence 3.4 The Combination of Multicomponent Reactions 4 Palladium-Catalyzed Isocyanide Reactions 5 The Quest for Stereoselective Multicomponent Reactions 6 Conclusion. © Georg Thieme Verlag Stuttgart - New York.