Emerging and re‐emerging pathogens often stem from zoonotic origins, cycling between humans and animals, and are frequently vectored and maintained by hematophagous arthropod vectors. The efficiency by which these disease agents are successfully transmitted between vertebrate hosts is influenced by many factors, including the host on which a vector feeds. The Lyme disease bacterium Borrelia burgdorferi sensu lato has adapted to survive in complex host environments, vectored by Ixodes ticks, and maintained in multiple vertebrate hosts. The versatility of Lyme borreliae in disparate host milieus is a compelling platform to investigate mechanisms dictating pathogen transmission through complex networks of vertebrates and ticks. Squamata, one of the most diverse clade of extant reptiles, is comprised primarily of lizards, many of which are readily fed upon by Ixodes ticks. Yet, lizards are one of the least studied taxa at risk of contributing to the transmission and life cycle maintenance of Lyme borreliae. In this review, we summarize the current evidence, spanning from field surveillance to laboratory infection studies, supporting their contributions to Lyme borreliae circulation. We also summarize the current understanding of divergent lizard immune responses that may explain the underlying molecular mechanisms to confer Lyme spirochete survival in vertebrate hosts. This review offers a critical perspective on potential enzootic cycles existing between lizard‐tick‐Borrelia interactions and highlights the importance of an eco‐immunology lens for zoonotic pathogen transmission studies. Lyme disease bacteria have adapted to survive diverse environments including ticks and a wide array of birds, small rodents, and lizards. Lizards are the least studied among these hosts. Here, we reviewed current paradigms of lizards' roles in the Lyme disease bacterial enzootic cycle. We further used lizards as a model to imply how the presence of a vertebrate host may mechanistically impact the transmission of a vector‐borne pathogen from molecular to ecological levels.