This article evaluates ovarian cancer cell lines as models for high-grade serous ovarian cancer (HGSOC) by comparing their genomic profiles with those of tumor samples. The study uses data from The Cancer Genome Atlas (TCGA) and the Broad-Novartis Cancer Cell Line Encyclopedia (CCLE) to analyze 47 ovarian cancer cell lines. The results show that many commonly used cell lines have significant differences in genetic profiles compared to HGSOC tumor samples. The study identifies several less commonly used cell lines that more closely resemble HGSOC tumor profiles and recommends them as better models for in vitro studies of HGSOC. Ovarian cancer is the most lethal gynaecological malignancy and the fifth leading cause of cancer death for women in the United States. It is traditionally divided into four histological subtypes, with HGSOC being the most aggressive and responsible for most ovarian cancer deaths. Recent research has shown that ovarian cancer is highly heterogeneous and may originate from different tissues, not just the ovary. The study found that the most commonly used cell lines for ovarian cancer, such as SK-OV-3, A2780, OVCAR-3, CAOV3, and IGROV1, have significant differences in their genomic profiles compared to HGSOC tumor samples. These cell lines often have flat copy-number profiles and mutations in genes not typically associated with HGSOC. In contrast, several less commonly used cell lines were found to have genomic profiles more similar to HGSOC tumors. The study also found that some cell lines, such as IGROV1, have a hypermutator genotype and may originate from different ovarian cancer subtypes. Expression profiles of these cell lines were compared with tumor samples, and it was found that some cell lines cluster with endometrial or clear cell ovarian cancer cell lines, suggesting they may not be of HGSOC origin. The study concludes that the choice of cell lines as models for HGSOC is crucial for preclinical research, as the genomic profiles of cell lines can significantly differ from those of tumor samples. The study recommends using cell lines that more closely resemble HGSOC tumor profiles for in vitro studies. The findings highlight the importance of using genomically informed choices when selecting cell lines for research, as this can improve the accuracy of preclinical studies and increase the likelihood of successful clinical translation.This article evaluates ovarian cancer cell lines as models for high-grade serous ovarian cancer (HGSOC) by comparing their genomic profiles with those of tumor samples. The study uses data from The Cancer Genome Atlas (TCGA) and the Broad-Novartis Cancer Cell Line Encyclopedia (CCLE) to analyze 47 ovarian cancer cell lines. The results show that many commonly used cell lines have significant differences in genetic profiles compared to HGSOC tumor samples. The study identifies several less commonly used cell lines that more closely resemble HGSOC tumor profiles and recommends them as better models for in vitro studies of HGSOC. Ovarian cancer is the most lethal gynaecological malignancy and the fifth leading cause of cancer death for women in the United States. It is traditionally divided into four histological subtypes, with HGSOC being the most aggressive and responsible for most ovarian cancer deaths. Recent research has shown that ovarian cancer is highly heterogeneous and may originate from different tissues, not just the ovary. The study found that the most commonly used cell lines for ovarian cancer, such as SK-OV-3, A2780, OVCAR-3, CAOV3, and IGROV1, have significant differences in their genomic profiles compared to HGSOC tumor samples. These cell lines often have flat copy-number profiles and mutations in genes not typically associated with HGSOC. In contrast, several less commonly used cell lines were found to have genomic profiles more similar to HGSOC tumors. The study also found that some cell lines, such as IGROV1, have a hypermutator genotype and may originate from different ovarian cancer subtypes. Expression profiles of these cell lines were compared with tumor samples, and it was found that some cell lines cluster with endometrial or clear cell ovarian cancer cell lines, suggesting they may not be of HGSOC origin. The study concludes that the choice of cell lines as models for HGSOC is crucial for preclinical research, as the genomic profiles of cell lines can significantly differ from those of tumor samples. The study recommends using cell lines that more closely resemble HGSOC tumor profiles for in vitro studies. The findings highlight the importance of using genomically informed choices when selecting cell lines for research, as this can improve the accuracy of preclinical studies and increase the likelihood of successful clinical translation.