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The impact of the microenvironment on innate lymphoid cell (ILC)-mediated immunity in humans remains largely unknown.Here we used full-length Smart-seq2 single-cell RNA-sequencing to unravel tissue-specific transcriptional profiles and heterogeneity of CD127+ ILCs across four human tissues.Correlation analysis identified gene modules characterizing the migratory properties of tonsil and blood ILCs,and signatures of tissue-residency,activation and modified metabolism in colon and lung ILCs.Trajectory analysis revealed potential differentiation pathways from circulating and tissue-resident na(i)ve ILCs to a spectrum of mature ILC subsets.In the lung we identified both CRTH2+ and CRTH2-ILC2 with lung-specific signatures,which could be recapitulated by alarmin-exposure of circulating ILC2.Finally,we describe unique TCR-V(D)J-rearrangement patterns of blood ILC1-like cells,revealing a subset of potentially immature ILCs with TCR-δ rearrangement.Our study provides a useful resource for in-depth understanding of ILC-mediated immunity in humans,with implications for disease.