Azaphilone, biosynthesized by polyketide synthase, is a class of fungal metabolites. In this review, after brief introduction of the natural azaphilone diversity, we in detail discussed azaphilic addition reaction involving conversion of natural azaphilone into the corresponding azaphilone alkaloid. Then, setting red Monascus pigments (a traditional food colorant in China) as example, we presented a new strategy, i.e., interfacing azaphilic addition reaction with living microbial metabolism in a one-pot process, to produce azaphilone alkaloid with a specified amine residue (red Monascus pigments) during submerged culture. Benefit from the red Monascus pigments with a specified amine residue, the influence of primary amine on characteristics of the food colorant was highlighted. Finally, the progress for screening of alternative azaphilone alkaloids (production from interfacing azaphilic addition reaction with submerged culture of Talaromyces sp. or Penicillium sp.) as natural food colorant was reviewed. KEY POINTS: * Azaphilic addition reaction of natural azaphilone is biocompatible * Red Monascus pigment is a classic example of azaphilone alkaloids * Azaphilone alkaloids are alterative natural food colorant. CI - (c) 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.