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Generation of the first T lymphocytes in the human embryo involves the emergence, migration, and thymus seeding of lymphoid progenitors together with concomitant thymus organogenesis, which is the initial step to establish the entire adaptive immune system. However, the cellular and molecular programs regulating this process remain unclear. We constructed a single-cell transcriptional landscape of human early T lymphopoiesis by using cells from multiple hemogenic and hematopoietic sites spanning embryonic and fetal stages. Among heterogenous early thymic progenitors, one subtype shared common features with a subset of lymphoid progenitors in fetal liver that are known as thymus-seeding progenitors. Unbiased bioinformatics analysis identified a distinct type of pre-thymic lymphoid progenitors in the aorta-gonad-mesonephros (AGM) region. In parallel, we investigated thymic epithelial cell development and potential cell-cell interactions during thymus organogenesis. Together, our data provide insights into human early T lymphopoiesis that prospectively direct T lymphocyte regeneration, which might lead to development of clinical applications. • Single-cell RNA-seq resolves human early T lymphopoiesis and thymus organogenesis • The first ETPs in the thymus share transcriptional features of TSPs in human fetal liver • Pre-thymic lymphoid progenitors are transcriptomically identified in human AGM region • Cortical TECs mature earlier than medullary TECs in human thymic primordium A comprehensive and precise understanding of early T lymphopoiesis and thymus organogenesis in human embryo is lacking. By performing single-cell transcriptomic analysis on human embryonic and fetal hematopoietic organs, Zeng et al. reveal distinct subpopulations of early thymic progenitors, identify thymus-seeding progenitors in fetal liver and pre-thymic lymphoid progenitors in the aorta-gonad-mesonephros region, and characterize early development of thymic epithelial cells. [ABSTRACT FROM AUTHOR]