<jats:title>Abstract</jats:title><jats:p>Natural products have enormous structural diversity, yet little is known about how such diversity is achieved in nature. Here we report the structural diversification of a cyanotoxin—lyngbyatoxin A—and its biosynthetic intermediates by heterologous expression of the <jats:italic>Streptomyces</jats:italic>‐derived <jats:italic>tleABC</jats:italic> biosynthetic gene cluster in three different <jats:italic>Streptomyces</jats:italic> hosts: <jats:italic>S. lividans</jats:italic>, <jats:italic>S. albus</jats:italic>, and <jats:italic>S. avermitilis</jats:italic>. Notably, the isolated lyngbyatoxin derivatives, including four new natural products, were biosynthesized by crosstalk between the heterologous <jats:italic>tleABC</jats:italic> gene cluster and the endogenous host enzymes. The simple strategy described here has expanded the structural diversity of lyngbyatoxin A and its biosynthetic intermediates, and provides opportunities for investigation of the currently underestimated hidden biosynthetic crosstalk.