Tuberculosis (TB) is a persistent infectious disease that threatens the health of people and numerous mammalian animal species worldwide. Estimates are that 9 million new human TB cases occur annually while animal illness rates are higher but the actual numbers are unknown. Epidemiology studies indicate that transmission among close contacts is the driving force behind TB epidemics. Until successfully treated or until infected animals are removed, cases will continue to transmit bacilli to contacts. Since antibiotic treatment for most infected animals is not practical, and a vaccine that generates sterilizing immunity has not been developed, a vaccine that controls disease transmission may be the current best path forward. Unlike rodents, infected larger animals including cattle and non-human primates (NHPs) can effectively transmit the bacilli to naïve hosts via the aerosol route; however, routine work with statistically significant numbers of cattle and NHPs is cost-prohibitive. Thus, an appropriate small animal TB transmission model for assessing vaccines is needed. Ferrets are widely employed to study the transmissibility of influenza viruses and other respiratory agents, but thus far, no studies examining these parameters for Mycobacterium bovis (Mb) and M. tuberculosis (Mtb) have been reported. We know that mice and guinea pigs intratracheally or intravenously infected with virulent Mtb and Mb bacilli develop acute disease and ultimately succumb. This is not the disease process observed in humans and animals in natural settings. In high-exposure locations, TB contacts have been found to develop acute disease but remain TST-negative and free of the pathogen, remain TST-negative but carry viable bacilli in their airways, or become TST-positive but remain culture negative. In other words, natural transmission results in variable disease responses. Our team has generated exciting preliminary data demonstrating that ferrets can become infected when given intratracheal Mtb bacilli, but most importantly, transmission occurs when infected transmitter animals interact with naïve sentinels co-housed over the course of at least 2 mo. Additionally, the TB disease states described above also are observed in naturally-infected ferrets.