Laboratory diagnosis of classic and emerging tick-borne rickettsial diseases is an important component of patient care and surveillance. However, in most instances confirmatory diagnosis relies on less than ideal serologic assays with limited sensitivity and temporal dependence and little utility for point-of-care treatment. This presentation will focus on a concise discussion of contemporary approaches to clinically-relevant diagnoses of rickettsioses. In particular, this imperative will be articulated for both acute stage agent specific diagnostic assays and a systems biology approach to host responses and evaluating specific biomarkers of disease and exposure.