Tick-borne disease (TBD) transmission foci need to be characterized in space and time, and are often discontinuous on both scales. An active TBD focus is dependent on the fulfillment of three conditions: tick survival, pathogen survival and opportunities for human exposure. The essentials for tick survival include food sources, reproduction, and protection from environmental extremes. The pathogen survival kit includes sufficient densities of ticks and suitable reservoir hosts, and opportunities for transmission between them in order to maintain infection. Opportunities for human exposure depend on sufficient number of encounters between ticks and humans. Because tick foci need to be described on a range of spatial and temporal resolutions, data for such characterization include a variety of surveillance data, field and laboratory experimental data, as well as results of statistical and mathematical analysis and modeling. The application of new tools from molecular biology, geographic information systems (GIS), and satellite imagery, in conjunction with appropriate analytical methods allow for detection of unknown foci and prediction of new ones. A long-term multi-scale study of Ixodes scapularis and Lyme disease in the north-central U. S. is reviewed. Diverse surveillance methods of ticks, rodents, deer, canids and humans were coupled with environmental characterization in situ to create a habitat profile for Lyme disease ticks. Incorporating various digitized databases, a statistical model was used to develop a risk map for tick distribution in the region. The process of introduction and establishment of new tick foci along the Illinois River is described in relation to the known tick distribution and predictions of invasion based on the risk model.