Advances in biology-driven therapy for high-grade serous ovarian cancer (HGSOC) have transformed treatment approaches. The completion of genome sequencing and a shift in understanding the cell of origin for HGSOC have led to new insights into its biology and therapeutic options. Experimental models have been revisited, and new tools developed. Key pathways, such as VEGF-driven angiogenesis and homologous recombination deficiency, have been identified as drivers of tumorigenesis. Molecular profiling of ovarian cancer subtypes has enabled personalized treatment strategies. PARP inhibitors (PARPis) have shown significant clinical benefit in selected patients, while research into resistance mechanisms is uncovering new therapeutic possibilities. HGSOC accounts for 70% of all ovarian cancers and is associated with significant mortality. It originates from the fallopian tube epithelium, not the ovarian surface epithelium, as supported by the discovery of serous tubal intraepithelial carcinomas (STICs). Genetic alterations, including TP53 mutations and BRCA1/2 mutations, are central to HGSOC development. Over 50% of HGSOC cases are homologous recombination deficient (HRD), which has critical therapeutic implications. Genetic and nongenetic factors, including TP53 mutations, BRCA1/2 mutations, and copy number changes, drive HGSOC. Transcription factors regulate gene expression programs and therapy response. Experimental models, including cell lines and animal models, have been developed to study HGSOC biology and test therapies. Metastasis and the tumor microenvironment (TME) are key aspects of HGSOC. The unique pattern of invasion and metastasis is influenced by interactions between cancer cells and the peritoneal environment. The TME plays a critical role in immune evasion and resistance to therapy. Advances in therapy include the use of PARP inhibitors, which target HRD in HGSOC, and anti-angiogenic agents like bevacizumab. These therapies have improved outcomes for patients with HGSOC. However, resistance mechanisms remain a challenge, and new strategies are being explored to overcome resistance. Future directions include improving early diagnosis, developing targeted therapies for HR-proficient cancers, and exploring combination therapies. Advances in immunotherapy and understanding of the cold TME are also critical. Biological discoveries are driving progress in therapies for this deadly cancer.Advances in biology-driven therapy for high-grade serous ovarian cancer (HGSOC) have transformed treatment approaches. The completion of genome sequencing and a shift in understanding the cell of origin for HGSOC have led to new insights into its biology and therapeutic options. Experimental models have been revisited, and new tools developed. Key pathways, such as VEGF-driven angiogenesis and homologous recombination deficiency, have been identified as drivers of tumorigenesis. Molecular profiling of ovarian cancer subtypes has enabled personalized treatment strategies. PARP inhibitors (PARPis) have shown significant clinical benefit in selected patients, while research into resistance mechanisms is uncovering new therapeutic possibilities. HGSOC accounts for 70% of all ovarian cancers and is associated with significant mortality. It originates from the fallopian tube epithelium, not the ovarian surface epithelium, as supported by the discovery of serous tubal intraepithelial carcinomas (STICs). Genetic alterations, including TP53 mutations and BRCA1/2 mutations, are central to HGSOC development. Over 50% of HGSOC cases are homologous recombination deficient (HRD), which has critical therapeutic implications. Genetic and nongenetic factors, including TP53 mutations, BRCA1/2 mutations, and copy number changes, drive HGSOC. Transcription factors regulate gene expression programs and therapy response. Experimental models, including cell lines and animal models, have been developed to study HGSOC biology and test therapies. Metastasis and the tumor microenvironment (TME) are key aspects of HGSOC. The unique pattern of invasion and metastasis is influenced by interactions between cancer cells and the peritoneal environment. The TME plays a critical role in immune evasion and resistance to therapy. Advances in therapy include the use of PARP inhibitors, which target HRD in HGSOC, and anti-angiogenic agents like bevacizumab. These therapies have improved outcomes for patients with HGSOC. However, resistance mechanisms remain a challenge, and new strategies are being explored to overcome resistance. Future directions include improving early diagnosis, developing targeted therapies for HR-proficient cancers, and exploring combination therapies. Advances in immunotherapy and understanding of the cold TME are also critical. Biological discoveries are driving progress in therapies for this deadly cancer.