Covering: up to the end of 2022The area of scalemic natural products is often enigmatic from a mechanistic standpoint, since low optical purity is observed in compounds having multiple contiguous stereogenic centers resulting from mechanistically distinct biogenetic steps. A scalemic state is rarely the result of a sloppy enzymatic activity, rather resulting from the expression of antipodal enzymes/directing proteins or from the erosion of optical purity by enzymatic or spontaneous reactions. Evidence for these processes is critically reviewed, identifying the mechanisms most often associated to the enzymatic generation of scalemic natural products and also discussing analytical exploitations of natural products' scalemicity.