The series of molecular events comprising the metastatic cascade in peritoneal carcinomatosis is complex. The tumor microenvironment is rich in factors regulating cell proliferation, DNA repair, and senescence. Combined hyperthermia and intraperitoneal chemotherapy are utilized in conjunction with cytoreductive surgery for peritoneal surface malignancies with the intent of producing an enhanced tumoricidal effect. Cellular stress and histologic alterations occur on the molecular level with microenvironmental selective pressures shaping gene expression, DNA damage response, and protein expression. Understanding these processes may be crucial to improving patient selection and in developing potential targeted therapies. This chapter focuses on the scientific rationale behind hyperthermic intraperitoneal chemotherapy (HIPEC) as anticancer therapy as well as the molecular and genetic considerations surrounding the use of HIPEC.