Recent research into the role of microRNA (miR) in the immune system has identified the miR-29 family as critical regulators of key processes in adaptive immunity. The miR-29 family consists of four members with shared regulatory capacity, namely miR-29a, miR-29b-1, miR-29b-2 and miR-29c. Being expressed in both T and B cells, as well as the main accessory cell types of thymic epithelium and dendritic cells, the miR-29 family has been identified as a putative regulator of immunity due to the predicted suppression of key immunological pathways. The generation of a series of in vivo molecular tools targeting the miR-29 family has identified the critical role of these miR in setting the molecular threshold for three central events in adaptive immunity: (1) control over thymic production of T cells by modulating the threshold for infection-associated thymic involution, (2) creating a neutral threshold for T cell polarization following activation, and (3) setting the threshold for B cell oncogenic transformation. These results identify the miR-29 family as potent immune modulators which have already been exploited through the evolution of a viral mimic and could potentially be exploited further for therapeutic intervention.