Borrelia burgdorferi sensu lato species complex is capable of establishing persistent infections in a wide variety of species, particularly rodents. Infection is asymptomatic or mild in most reservoir host species, indicating successful co-evolution of the pathogen with its natural hosts. However, infected humans and other incidental hosts can develop Lyme disease, a serious inflammatory syndrome characterized by tissue inflammation of joints, heart, muscles, skin, and CNS. Although B. burgdorferi infection induces both innate and adaptive immune responses, they are ultimately ineffective in clearing the infection from reservoir hosts, leading to bacterial persistence. Here, we review some mechanisms by which B. burgdorferi evades the immune system of the rodent host, focusing in particular on the effects of innate immune mechanisms and recent findings suggesting that T-dependent B cell responses are subverted during infection. A better understanding of the mechanisms causing persistence in rodents may help to increase our understanding of the pathogenesis of Lyme disease and ultimately aid in the development of therapies that support effective clearance of the bacterial infection by the host’s immune system.