Many polyketides isolated from marine sponges are generated by symbiotic microorganisms via trans-AT polyketide synthases. Cloning the biosynthetic gene clusters of biologically active polyketides using metagenomics not only elucidates the biosynthetic pathways of bioactive compounds, but also makes it possible to obtain the target compounds by heterologous expression. This review presents recent progresses on the biosynthesis of polyketides derived by trans-AT polyketide synthases (PKSs) and related biosynthetic pathways in marine sponges.