Polarized T helper cell (Th cell) responses are important determinants of host protection. Th cell subsets tailor their functional repertoire of cytokines to their cognate antigens to efficiently contribute to their clearance. In contrast, in settings of immune abrogation, these polarized cytokine patterns of Th cells can mediate tissue damage and pathology resulting in allergy or autoimmunity. Recent technological developments in single-cell genomics and proteomics as well as advances in the high-dimensional bioinformatic analysis of complex datasets have challenged the prevailing Th cell subset classification into Th1, Th2, Th17, and other subsets. Additionally, systems immunology approaches have revealed that instructive input from the peripheral tissue microenvironment can have differential effects on the overall phenotype and molecular wiring of Th cells depending on their spatial distribution. Th cells from the blood or secondary lymphoid organs are therefore expected to follow distinct rules of regulation. In this review, the functional heterogeneity of Th cell subsets will be reviewed in the context of new technological developments and T-cell compartmentalization in tissue niches. This work will especially focus on challenges to the traditional boundaries of Th cell subsets and will discuss the underlying regulatory checkpoints, which could reveal new therapeutic strategies for various immune-mediated diseases.