Pipecolic acid is an important precursor of many useful microbial secondary metabolites. Pipecolic acid-derived moieties are often crucial for the biological activities of some microbial natural products with pharmaceutical applications. Understanding the biogenesis of pipecolic acid in microorganisms would be a significant step toward the mutasynthesis of novel analogs of choice. This review focuses on various microbial pathways and enzymes for pipecolic acid synthesis, especially those related to the origination of pipecolic acid moieties in secondary metabolites.