Orthotopic PDX models have gained prominence in basic and translational cancer research because they are more clinically relevant than traditional subcutaneous or cell-line-derived PDX models. They preserve the histological architecture, stroma construction, and gene-expression or mutation status of original tumor tissue and they replicate the human tumor microenvironment, which is critical to cancer progression and metastasis. O-PDX models can predict the development of resistance to first-line therapy and response to second-line therapy — before these events are observed in patients.