There is an emerging body of research demonstrating that the co-expression of key lineage-specifying transcription factors, commonly referred to as 'master regulators', affects the functional capabilities and flexibility of CD4⁺ T cell subsets. Here, we discuss how the natural co-expression of these lineage-specifying transcription factors has challenged the concept that the expression of a single 'master regulator' strictly establishes an absolute CD4⁺ T cell phenotype. Instead, it is becoming clear that the interplay between the lineage-specifying (or lineage-defining) transcription factors, including T-bet, GATA3, RORγt, BCL-6 and FOXP3, contributes to the fate and flexibility of CD4⁺ T cell subtypes. This in turn has led to the realization that CD4⁺ T cell phenotypes are more diverse than previously recognized.