Soil microbiomes are a rich source of uncharacterized natural product biosynthetic gene clusters. Here we use short conserved biosynthetic gene sequences (natural product sequence tags) amplified from soil microbiomes as phylogenetic markers to correlate genotype to chemotype and target the discovery of novel bioactive pentangular polyphenols from the environment. The heterologous expression of an environmental DNA-derived gene cluster (the ARX cluster), whose ketosynthase beta (KSβ) sequence tag was phylogenetically distinct from any known KSβ sequence, led to the discovery of the arixanthomycins. Arixanthomycin A (1) exhibits potent antiproliferative activity against human cancer cell lines.