MicroRNAs (miRNAs) are a newly recognized class of regulatory genes which repress the expression of protein‐coding genes. Numerous studies have uncovered a complex role for miRNAs regulating many aspects of a variety of cellular processes including cell growth, differentiation, and lineage commitment. In the immune system, miR‐155 is unique in its ability to shape the transcriptome of activated myeloid and lymphoid cells controlling diverse biological functions ranging from inflammation to immunological memory. Not surprisingly, a tight control of miR‐155 expression is required to avoid malignant transformation, as evidenced by miR‐155 overexpression in many cancers of B‐cell origin. In this review, we discuss the potential of miR‐155 as a molecular target for therapeutic intervention and discuss the function of miR‐155 in the context of protective immunity. We first look back into the emergence of miR‐155 in evolution, which is coincidental with the emergence of the ancestors of the antigen receptors. We then summarize what we have learned about the role of miR‐155 in the regulation of lymphoid subsets at the cellular and molecular level in the context of recent progress in this field.