Tick-borne co-infections are becoming increasingly appreciated as causes of human disease and morbidity. Once thought to be relatively rare, researchers are now finding that co-infection of ticks, such as Ixodes scapularis, occurs “more frequently than expected, resulting in enhanced human exposure to multiple infections that can cause more severe symptoms and sometimes make diagnosis more difficult” [Dunn 2014]. This knowledge has helped clinicians better define the often complex presentation of patients with persistent tick-borne disease and opened new pathways for effective treatment and management of these patients. Along with this greater understanding of the frequency of tick co-infection, other researchers have also looked for more effective treatment approaches for persistent co-infections. In the past 3 years there have been research breakthroughs in the utilization of both pharmacologic and botanical anti-microbials that have led to significant improvements in patient outcomes, decreased patient suffering and decreased burden of illness to society.