The study by Treutlein et al. uses single-cell RNA sequencing (scRNA-seq) to reconstruct the lineage hierarchy of distal lung epithelium in mice. The researchers sequenced 198 individual cells at four developmental stages, from early to late alveolar differentiation, to identify transcriptional states that define the developmental and cellular hierarchy of the distal lung epithelium. They classified cells into distinct groups using an unbiased genome-wide approach, confirming the classical model of epithelial cell type diversity and identifying novel cell type markers and transcriptional regulators. The analysis revealed the molecular steps during the maturation of bipotential progenitors along both alveolar lineages and the full lifecycle of the alveolar type 2 cell lineage. The single-cell genomics approach is applicable to any developing or mature tissue, enabling the delineation of molecularly distinct cell types, definition of progenitors and lineage hierarchies, and identification of lineage-specific regulatory factors. The study also explored temporal changes within the distal lung, showing that AT2 cell maturation occurs in a progressive manner via transcriptionally distinct intermediates.The study by Treutlein et al. uses single-cell RNA sequencing (scRNA-seq) to reconstruct the lineage hierarchy of distal lung epithelium in mice. The researchers sequenced 198 individual cells at four developmental stages, from early to late alveolar differentiation, to identify transcriptional states that define the developmental and cellular hierarchy of the distal lung epithelium. They classified cells into distinct groups using an unbiased genome-wide approach, confirming the classical model of epithelial cell type diversity and identifying novel cell type markers and transcriptional regulators. The analysis revealed the molecular steps during the maturation of bipotential progenitors along both alveolar lineages and the full lifecycle of the alveolar type 2 cell lineage. The single-cell genomics approach is applicable to any developing or mature tissue, enabling the delineation of molecularly distinct cell types, definition of progenitors and lineage hierarchies, and identification of lineage-specific regulatory factors. The study also explored temporal changes within the distal lung, showing that AT2 cell maturation occurs in a progressive manner via transcriptionally distinct intermediates.