Covering up to 2013. Cofactor-dependent enzymes which need small organic molecule cofactors to accomplish enzymatic activity are widespread. The number of newly discovered reactions within cofactor-dependent enzyme families increases continuously. A knowledge based categorization of cofactors with respect to their chemical properties shows that within enzymes they are not used for the catalysis of singular types of reactions and functionalities. Therefore, in many cases an unambiguous and narrow classification does not seem sufficient. Rather, the functional diversity of cofactors found in enzymes represents variations around specific themes with regard to a catalysed reaction and the cofactor chemistry. Furthermore, organic cofactor molecules are also used for non-enzymatic functions. Two representative cofactors are exemplarily discussed in detail, thiamin diphosphate (ThDP) as a self-sufficient cofactor and S-adenosyl-L-methionine (SAM), as both a catalytic and building-block-delivering cofactor. A further synopsis on selected examples of organic cofactors emphasizes the discovery and application of new enzymatic activities based on the cofactor-dependent chemistry and shows how bioinspired synthesis approaches expand catalytic and non-catalytic synthesis applications beyond natural solutions.