Eutopic endometrium in endometriosis has molecular evidence of resistance to progesterone (P₄) and activation of the PKA pathway in the stromal compartment. To investigate global and temporal responses of eutopic endometrium to P₄, we compared early (6-h), intermediate (48-h), and late (14-Day) transcriptomes, signaling pathways, and networks of human endometrial stromal fibroblasts (hESF) from women with endometriosis (hESF_endo) with hESF from women without endometriosis (hESF_nonendo). Endometrial biopsy samples were obtained from subjects with and without mild peritoneal endometriosis (n = 4 per group), and hESF were isolated and treated with P₄ (1 μM) plus estradiol (E₂) (10 nM), E₂ alone (10 nM), or vehicle for up to 14 days. Total RNA was subjected to microarray analysis using a Gene 1.0 ST (Affymetrix) platform and analyzed by using bioinformatic algorithms, and data were validated by quantitative real-time PCR and ELISA. Results revealed unique kinetic expression of specific genes and unique pathways, distinct biological and molecular processes, and signaling pathways and networks during the early, intermediate, and late responses to P₄ in both hESF_nonendo and hESF_endo, although a blunted response to P₄ was observed in the latter. The normal response of hESF to P₄ involves a tightly regulated kinetic cascade involving key components in the P₄ receptor and MAPK signaling pathways that results in inhibition of E₂-mediated proliferation and eventual differentiation to the decidual phenotype, but this was not established in the hESF_endo early response to P₄. The abnormal response of this cell type to P₄ may contribute to compromised embryonic implantation and infertility in women with endometriosis.