The peritoneum consists of a layer of mesothelial cells covering all abdominal organs and the abdominopelvic wall. Peritoneal metastases are formed after exfoliation of free tumor cells from a primary tumor invading the peritoneum. Consequently, most peritoneal metastases originate from abdominal organs such as the colon, rectum, stomach, or ovaria. Cancer cells spread in the abdominal cavity resulting from the natural flow of intraperitoneal fluids and subsequently outgrow into multiple nodular metastases on the peritoneum. Peritoneal metastases remain one of the most oncological challenges in current treatment of various intra-abdominal malignancies [1]. Current systemic palliative chemotherapeutic regimes appear to have only a limited effect in treating peritoneal metastases, both in improving survival and decreasing symptoms of peritoneal metastases such as bowel obstruction or the formation of disabling amounts of ascites. New treatment strategies involving cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy have shown favorable results in numerous intraperitoneal metastasizing intra-abdominal malignancies, such as appendiceal and colorectal cancer. Following the randomized controlled trial by Verwaal et al. [2], cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with limited peritoneal metastases of colorectal cancer (CRC) is now regarded as standard treatment in selected patients (no extraperitoneal disease and sufficient performance status). The goal of cytoreductive surgery (CRS) is to remove all macroscopic malignant disease by performing several visceral resections and peritonectomy procedures. This is followed by a 30–90 min intraperitoneal perfusion of the abdominal cavity using heated chemotherapy. The aim of this so-called hyperthermic intraperitoneal chemotherapy (HIPEC) is to eradicate any remaining microscopic tumor cells. The chemotherapy is generally heated up to 41–43 °C. This is performed for several reasons; first in vitro cancer cells sensitivity is increased in many chemotherapeutic drugs. Additionally, some studies have shown improved pharmacokinetics of chemotherapy in hyperthermic conditions. Currently, various chemotherapeutic drugs, such as mitomycin or cisplatin, are used for HIPEC. Several factors influence the selection of the appropriate drug selection for the use in intraperitoneal chemotherapy. Important drug characteristics are systemic activity in the treating malignancy, concentration-related cytotoxicity, hyperthermic synergy, favorable intraperitoneal pharmacokinetics, adequate tissue penetration, acceptable local and systemic toxicity, and the safety of administration for hospital personnel. Drugs with a direct cytotoxic effect, i.e., not cell cycle specific, will have more potential as in HIPEC the exposure time of the chemotherapeutic drug is limited, and multiple administrations are not feasible in HIPEC. Different chemotherapeutic drugs, and combinations of these, are used for the use in intraperitoneal chemotherapeutic treatment. Table 2.1 gives an overview of current or investigated drugs for HIPEC treatment. The goal of the current chapter is to provide a comprehensive overview on the selection of chemotherapeutic drugs for intraperitoneal chemotherapy in various malignancies.