The problem of cancer treatment resistance persists, and trustworthy preclinical models are limited. Using high-grade serous ovarian cancer (HGSC) as a case study, researchers investigated this unfulfilled demand. Through full genome sequencing, RNA sequencing, and the development of intraperitoneal models, they could characterize the complete cell panel and generate 5 in vitro and 2 in vivo platinum-resistant HGSC models. Through mutational signature analysis, they deduced that drug-resistant platinum-resistant cell lines originated from a common ancestor clone but were unable to pinpoint the specific mutation or mutations responsible for this resistance. However, cells resistant to cisplatin and carboplatin saw repeated alterations in gene expression that significantly corresponded with those seen in independent samples from numerous individuals with relapsed HGSC. Human resistant/refractory samples and those resistant to cisplatin and carboplatin showed a consistent enrichment of Gene Ontology Biological Pathways (GOBPs) associated with the tumor microenvironment, especially the extracellular matrix. However, the most significantly over-represented GOBP developed uniquely in either cisplatin- or carboplatin-resistant cell lines, resulting in varied intraperitoneal behaviors that mimic various clinical signs of recurrent human HGSC. Non-genetic factors have an essential role in developing resistance to chemotherapy, as shown by some clinically relevant and implementable models. Cancer cells that were resistant to treatment consistently expressed biological pathways that are involved with the extracellular matrix. This data demonstrates that the evolution of drug resistance is influenced by cancer cell-intrinsic mechanisms and that repeated alterations in gene expression provide a fitness advantage throughout platinum therapy. Potential treatment options for platinum-resistant HGSC may lie in the genes and pathways reported here.