The Borrelia burgdorferi infectious cycle requires that the organism adapt to vast differences in environmental conditions found in its tick and mammalian hosts. Previous studies have shown that B. burgdorferi accomplishes this accommodation in part by regulating expression of its surface proteins. Outer surface protein A (OspA) is a borrelial protein important in colonization of the tick midgut. OspA is up-regulated when the organism is in its tick host and down-regulated when it is in a mammalian host. However, little is known about how it is up-regulated again in a mammalian host in preparation for entry into a feeding tick. Here, we report that the host neuroendocrine stress hormones, epinephrine and norepinephrine, are specifically bound by B. burgdorferi and result in increased expression of OspA. This recognition is specific and blocked by competitive inhibitors of human adrenergic receptors. To determine whether recognition of catecholamines, which are likely to be present at the site of a tick bite, may play a role in preparing the organism for reentry into a tick from a mammalian host, we administered a beta-adrenergic blocker, propranolol, to infected mice. Propranolol significantly reduced uptake of B. burgdorferi by feeding ticks and decreased expression of OspA in B. burgdorferi recovered from ticks that fed on propranolol-treated mice. Our studies suggest that B. burgdorferi may co-opt host neuroendocrine signals to inform the organism of local changes that predict the presence of its next host and allow it to prepare for transition to a new environment.