Purpose: The relative importance of fallopian tube (FT) compared with ovarian surface epithelium (OSE) in the genesis of serous type of ovarian cancer (SOC) is still unsettled. Here, we followed an integrated approach to study the tissue origin of SOC, as well as its association with clinical outcome and response to therapeutic drugs. Experimental Design: A collection of transcriptome data of 80 FTs, 89 OSEs, and 2,668 SOCs was systematically analyzed to determine the characteristic of FT-like and OSE-like tumors. A molecular signature was developed for identifying tissue origin of SOC and then was used to reevaluate the prognostic genes and therapeutic biomarkers of SOC of different tissue origins. IHC staining of tissue array and functional experiments on a panel of ovarian cancer cell lines were used to further validate the key findings. Results: The expression patterns of tissue-specific genes, prognostic genes, and molecular markers all support a dualistic tissue origin of SOC, from either FT or OSE. A molecular signature was established to identify the tissue identity of SOCs. Surprisingly, the signature showed a strong association with overall survival (OSE-like vs. FT-like, HR = 4.16; 95% CI, 2.67–6.48; P < 10-). The pharmacogenomic approach revealed AXL to be a therapeutic target of the aggressive OSE-derived SOC. Conclusions: SOC has two subtypes originated from either FT or OSE, which show different clinical and pathologic features.