In the 1980s, the blacklegged tick, Ixodes scapularis Say, and rodents were recognized as the principal vector and reservoir hosts of the Lyme disease spirochete Borrelia burgdorferi in the eastern United States, and deer were incriminated as principal hosts for I. scapularis adults. These realizations led to pioneering studies aiming to reduce the risk for transmission of B. burgdorferi to humans by attacking host-seeking ticks with acaricides, interrupting the enzootic transmission cycle by killing immatures infesting rodent reservoirs by means of acaricide-treated nesting material, or reducing deer abundance to suppress tick numbers. We review the progress over the past three decades in the fields of: 1) prevention of human–tick contact with repellents and permethrin-treated clothing, and 2) suppression of I. scapularis and disruption of enzootic B. burgdorferi transmission with environmentally based control methods. Personal protective measures include synthetic and natural product-based repellents that can be applied to skin and clothing, permethrin sprays for clothing and gear, and permethrin-treated clothing. A wide variety of approaches and products to suppress I. scapularis or disrupt enzootic B. burgdorferi transmission have emerged and been evaluated in field trials. Application of synthetic chemical acaricides is a robust method to suppress host-seeking I. scapularis ticks within a treated area for at least 6–8 wk. Natural product-based acaricides or entomopathogenic fungi have emerged as alternatives to kill host-seeking ticks for homeowners who are unwilling to use synthetic chemical acaricides. However, as compared with synthetic chemical acaricides, these approaches appear less robust in terms of both their killing efficacy and persistence. Use of rodent-targeted topical acaricides represents an alternative for homeowners opposed to open distribution of acaricides to the ground and vegetation on their properties. This host-targeted approach also provides the benefit of the intervention impacting the entire rodent home range. Rodent-targeted oral vaccines against B. burgdorferi and a rodent-targeted antibiotic bait have been evaluated in laboratory and field trials but are not yet commercially available. Targeting of deer—via deer reduction or treatment of deer with topical acaricides—can provide area-wide suppression of host-seeking I. scapularis. These two deer-targeted approaches combine great potential for protection that impacts the entire landscape with severe problems relating to public acceptance or implementation logistics. Integrated use of two or more methods has unfortunately been evaluated in very few published studies, but additional field evaluations of integrated tick and pathogen strategies are underway.