Polarized helper T cells were once thought to represent stable lineages with limited or no potential to acquire features of alternative subsets. This notion was based on the study of long-term T cell clones. Accumulating evidence derived from in vivo studies and high-throughput analyses of histone modifications now suggests that CD4+ T cells, especially Th17 and CD4+ regulatory T cells, retain significant phenotypic plasticity. This is assumed to enhance their ability to adapt to changes in the tissue micro-environment offering increased functional flexibility. However, this evidence is based on short-term activated CD4+ T cells and it is uncertain whether these reliably reflect the full complement of T cell differentiation states found in vivo. As persistent T cell stimulation is common in chronic inflammatory diseases, we argue that the analysis of long-term cultured T cell lines and clones able to maintain a stable phenotype can supplement these studies and help resolve the true dimensions of the diversity of the adaptive immune response. The use of T cell populations with predictable behavior for in vivo adoptive transfer studies should allow proper assessment of the role of individual T cell subsets in immunemediated tissue damage.