Bioinformatics analyses have identified gene clusters encoding cryptic or orphan natural product biosynthetic pathways, not associated with the production of known metabolites, in numerous microbial genome sequences. Discovery of the products of such cryptic gene clusters promises to unearth a hitherto untapped wealth of novel bioactive compounds. I will describe our efforts to identify products of cryptic biosynthetic pathways in Streptomyces genomes. Insights from bioinformatics analyses into structural features of the products of cryptic pathways will be discussed. Examples of how such insights have been used to simplify the analytical challenge associated with discovering novel products of cryptic pathways will be detailed. Approaches to discovering products of cryptic pathways when no structural insights are available from bioinformatics will also be discussed. A major obstacle to the discovery of novel natural products by genome mining is that many cryptic pathways are silent under normal laboratory conditions. I will describe collaborative unpublished work that has overcome this problem and led to the discovery of a novel biologically active polyketide natural product.