Plasmacytoid dendritic cells (pDCs) are innate sentinels that produce type I interferons (IFN-I) during infection. Here, we ask how developmental stage and tissue context shape human pDC transcriptional states. Single-cell RNA sequencing of pDCs from blood, thymus, lymph nodes, and tonsils across fetal, infant, and pediatric stages reveals tissue-enriched programs, including IFN-I–imprinted pDCs in thymus, NFκB-imprinted pDCs in tonsils, and resting pDCs in blood and lymph nodes. Across tissues, we identify a conserved pDC subset characterized by prostaglandin D2 production and dopamine responsiveness, indicating a potential neuromodulatory axis. Cycling pDCs are abundant in fetal and infant lymphoid tissues and decline with age, while remaining enriched in bone marrow throughout life. Blastic pDC neoplasm is associated with enrichment of cycling, mutation-bearing pDCs in bone marrow, suggesting this niche serves as a reservoir for malignant pDCs. These findings define developmentally regulated and tissue-imprinted pDC programs that shape immune homeostasis and disease.