CD4 ⁺ T cells are crucial for directing appropriate immune responses during host defense and for the pathogenesis of inflammatory diseases. In addition to the classical biphasic model of differentiation of T-helper 1 (T _h 1) and T _h 2 cells, unexpected increases in the numbers of CD4 ⁺ T-cell subsets, including T _h 17, T _h 9, T follicular-helper (T _fh ) and T-regulatory (T _reg ) cells, have been recognized. In the present review, we focus on how these various T-helper cell subsets contribute to the pathogenesis of immune-mediated inflammatory diseases. In particular, we focus on multiple sclerosis, psoriasis and asthma as typical model diseases in which multiple T-helper cell subsets have recently been suggested to play a role. We will also discuss various unique sub-populations of T-helper cells that have been identified. First, we will introduce the heterogeneous T-helper cell subsets, which are classified by their simultaneous expression of multiple key transcription factors. We will also introduce different kinds of memory-type T _h 2 cells, which are involved in the pathogenesis of chronic type-2 immune-related diseases. Finally, we will discuss the molecular mechanisms underlying the generation of the plasticity and heterogeneity of T-helper cell subsets. The latest progress in the study of T-helper cell subsets has forced us to reconsider the etiology of immune-mediated inflammatory diseases beyond the model based on the T _h 1/T _h 2 balance. To this end, we propose another model—the pathogenic T-helper population disease-induction model—as a possible mechanism for the induction and/or persistence of immune-mediated inflammatory diseases.