Over the last 10 to 15 years, increasing evidence suggests that persistence of Listeria monocytogenes in food processing plants for years or even decades is an important factor in the transmission of this foodborne pathogen and the root cause of a number of human listeriosis outbreaks. L. monocytogenes persistence in other food-associated environments (e.g., farms and retail establishments) may also contribute to food contamination and transmission of the pathogen to humans. Although L. monocytogenes persistence is typically identified through isolation of a specific molecular subtype from samples collected in a given environment over time, formal (statistical) criteria for identification of persistence are undefined. Environmental factors (e.g., facilities and equipment that are difficult to clean) have been identified as key contributors to persistence; however, the mechanisms are less well understood. Although some researchers have reported that persistent strains possess specific characteristics that may facilitate persistence (e.g., biofilm formation and better adaptation to stress conditions), other researchers have not found significant differences between persistent and nonpersistent strains in the phenotypic characteristics that might facilitate persistence. This review includes a discussion of our current knowledge concerning some key issues associated with the persistence of L. monocytogenes, with special focus on (i) persistence in food processing plants and other food-associated environments, (ii) persistence in the general environment, (iii) phenotypic and genetic characteristics of persistent strains, (iv) niches, and (v) public health and economic implications of persistence. Although the available data clearly indicate that L. monocytogenes persistence at various stages of the food chain contributes to contamination of finished products, continued efforts to quantitatively integrate data on L. monocytogenes persistence (e.g., meta-analysis or quantitative microbial risk assessment) will be needed to advance our understanding of persistence of this pathogen and its economic and public health impacts.