Approaches to creating novel borrelidin analogues will be described. The polyketide macrolide borrelidin is a potent inhibitor of angiogenesis, with a number of unusual structural features. These include a cyclopentane carboxylic acid moiety at C17 and a nitrile moiety at C12 of the macrocyclic ring. The cloning of the borrelidin biosynthetic cluster has led to the identification of the genes involved in generating these unusual features and also to the discovery that iterative use of one of the modules is required in the formation of the core polyketide synthase. A set of novel borrelidin analogues prepared by precursor-directed biosynthesis will be described. Structure-activity relationship analysis suggests that the cytotoxic and anti-angiongenic activities can be differentiated by altering substituents at C17.