Multi-Component Reactions (MCRs) constitute a methodology to shorter syntheses of natural products or complex molecules similar to natural. Due to the large number of accessible compounds and other advantages, this type of chemistry has become very popular in the community of combinatorial chemists. In the last 5 years combinatorial chemistry is has evolved from the synthesis of libraries based on one scaffold to the synthesis of structurally diverse compounds, better known as diversity-oriented synthesis. Following this trend, the design of MCRs is becoming a tool kit for chemists to explore chemistry space broadly with complex and diverse structures. Various approaches to the creation of novel MCRs including "union of MCRs", "substrate design", and "reaction operator" are discussed here. © 2006 Wiley-VCH Verlag GmbH & Co. KGaA.