Five years after the initial observations implicating the T helper (Th)-cell dichotomy (Th1/Th2) as the focal point in the immunoregulation of murine infection with Leishmania major, investigation has shifted to the factors that govern the differentiation of a specific immune response from its pre-immune of undifferentiated state. In this article, Steven Reiner focuses on the most recent advances concerning the lineage commitment of mature Th-cell populations, showing how new techniques [such as polymerase chain reaction (PCR) and transgenic mice] have allowed for a more-careful dissection of the early evolution of an immune response.