Natural products from microorganisms are a crucial source for novel therapeutics. Even so, it seems that many valuable compounds are overlooked when culturing microbes under standardized laboratory conditions. Many biosynthesis genes remain silent and such "cryptic" or "orphan" pathways are only activated under specific conditions. This report gives an overview on the strategies to trigger biosynthetic pathways to yield "cryptic natural products" through external cues, co-cultivation and genomic approaches such as genome-mining, epigenetic remodeling, and engineered pathway activation.