Abstract T helper type 2 (Th2) cells are important regulators of mammalian adaptive immunity and have relevance for infection, auto-immunity and tumour immunology. Using a newly developed, genome-wide retroviral CRISPR knock-out (KO) library, combined with RNA-seq, ATAC-seq and ChIP-seq, we have dissected the regulatory circuitry governing activation (including proliferation) and differentiation of these cells. Our experiments distinguish cell activation versus differentiation in a quantitative framework. We demonstrate that these two processes are tightly coupled and are jointly controlled by many transcription factors, metabolic genes and cytokine/receptor pairs. There is only a small number of genes regulating differentiation without any role in activation. Our study provides an atlas for the T helper cell regulatory network, pinpointing key players of Th2 differentiation and demonstrating remarkable plasticity between the diverse T helper cell fates. We provide an online resource for interactive data querying at: http://data.teichlab.org .