Over the past several decades, the frequency of contact between humans and ticks has increased dramatically. Concomitantly, several newly recognized tick-borne pathogens have emerged joining those already known to be transmitted by ticks. Together these factors have led to an enhanced public health awareness of ticks, tick-borne agents, and their associated diseases. Reports that several of these agents are transmitted by blood transfusion have raised concerns about blood safety. The primary agents of interest are members of the genus Babesia, but Anaplasma phagocytophilum, Rickettsia rickettsii, Colorado tick fever virus, and tick-borne encephalitis virus also have been transmitted by transfusion. In many cases, these agents and their diseases share common features including vectors, symptoms, and diagnosis. Unfortunately, they also share the common problem of insufficient epidemiologic and transmissibility data necessary for making informed decisions regarding potential blood safety interventions. Although further surveillance and epidemiologic studies of tick-borne agents are clearly needed, at present only the Babesia warrant consideration for active intervention; because donor management strategies based on risk-factor questions are inadequate, leukoreduction not effective for agents found in red cells and pathogen inactivation remains problematic for red cell products. Despite the present unavailability of screening assays, some form of serologic and nucleic acid testing may be justified for the Babesia. Given that interactions between humans and ticks are likely to increase in the future, vigilance is required as new and extant tick-borne agents pose potential threats to transfusion safety.