Rickettsia rickettsii, known as the agent of Rocky Mountain spotted fever (RMSF), was originally described 100 years ago by Howard Ricketts in the Bitterroot Valley of western Montana. It is a New World pathogen, found throughout the Americas, and, although not the only pathogenic rickettsial species, it is the most commonly fatal. One of our challenges in developing assays is the fact the RMSF is too often diagnosed based upon antibody reactivity with R. rickettsii. This would sound straightforward, except that crossreactivity occurs throughout the spotted fever group, with the degree of crossreactivity being a function of genetic relatedness to other species found in the Americas.