Summary T helper type 2 (Th2) cells are important regulators of mammalian adaptive immunity and have relevance for infection, autoimmunity, and tumor immunology. Using a newly developed, genome-wide retroviral CRISPR knockout (KO) library, combined with RNA-seq, ATAC-seq, and ChIP-seq, we have dissected the regulatory circuitry governing activation 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 are only a small number of genes regulating differentiation without any role in activation. By combining biochemical and genetic data, we provide an atlas for Th2 differentiation, validating known regulators and identifying factors, such as Pparg and Bhlhe40 , as part of the core regulatory network governing Th2 helper cell fates. Graphical Abstract Highlights • A retroviral CRISPR sgRNA library enables screening in primary mouse T helper cells • Genes frequently affect both T helper cell activation and differentiation • Genes of all functional categories impact activation and differentiation • The transcription factor PPARG appears particularly important for Th2 gene regulation A CRISPR-based screen reveals gene networks central to modulating multiple aspects of Th2 cell function. [ABSTRACT FROM AUTHOR]