This chapter reviews and discusses (i) the human disease manifestations for major pathogenic groups, with some attention to detail on how these differ between genera and species within a single genus; (ii) the evolution of treatment for rickettsial infections; (iii) the existing challenges for treatment and management in human infections; and (iv) corroborated or suspected treatment failures or persistent clinical complaints. The underlying theme for disease manifestations in the Rickettsiaceae is systemic infection of endothelial cells, leading to increased vascular permeability. Once diagnosed, rickettsioses, ehrlichiosis, and anaplasmosis are primarily managed with specific antimicrobial agent therapy. The major advantage of doxycycline is its twice-daily oral dosing, as opposed to three or four doses daily for tetracycline. In general, tetracycline antibiotics are considered rickettsiastatic, not rickettsiacidal. This concept has led to several specific recommendations regarding treatment in rickettsial disease. First, treatment should be provided for long enough that immune recognition and clearance of active infection can proceed to eliminate viable although nonreplicating rickettsia surviving within intracellular niches. Second, since proper immune induction is in part dependent on rickettsial antigen mass, early therapy can sometimes simply suppress growth in the absence of waxing immunity, leading to relapse after apparent appropriate treatment doses and intervals. The identification of innate resistance owing to naturally occurring genetic mutations that confer resistance to currently useful antibiotics underscores the degree of genetic diversity observed in Rickettsiales genome projects.