The incidence of tick-borne diseases has increased in recent decades and accounts for the majority of vector-borne disease cases in temperate areas of Europe, North America, and Asia. This emergence has been attributed to multiple and interactive drivers including changes in climate, land use, abundance of key hosts, and people’s behaviors affecting the probability of human exposure to infected ticks. In this forum paper, we focus on how land use changes have shaped the eco-epidemiology of Ixodes scapularis-borne pathogens, in particular the Lyme disease spirochete Borrelia burgdorferisensu stricto in the eastern United States. We use this as a model system, addressing other tick-borne disease systems as needed to illustrate patterns or processes. We first examine how land use interacts with abiotic conditions (microclimate) and biotic factors (e.g., host community composition) to influence the enzootic hazard, measured as the density of host-seeking I. scapularisnymphs infected with B. burgdorferis.s. We then review the evidence of how specific landscape configuration, in particular forest fragmentation, influences the enzootic hazard and disease risk across spatial scales and urbanization levels. We emphasize the need for a dynamic understanding of landscapes based on tick and pathogen host movement and habitat use in relation to human resource provisioning. We propose a coupled natural-human systems framework for tick-borne diseases that accounts for the multiple interactions, nonlinearities and feedbacks in the system and conclude with a call for standardization of methodology and terminology to help integrate studies conducted at multiple scales.