Traditional anti-cancer treatments consist of chemotherapeutic drugs that effectively eliminate rapidly dividing tumor cells. However, in many cases chemotherapy fails to eliminate the tumor and even when chemotherapy is successful, its systemic cytotoxicity often results in detrimental side effects. To overcome these problems, many laboratories have focused on the design of novel therapies that exhibit tumor specific toxicity. The transferrin receptor (TfR), a cell membrane-associated glycoprotein involved in iron homeostasis and cell growth, has been explored as a target to deliver therapeutics into cancer cells due to its increased expression on malignant cells, accessibility on the cell surface, and constitutive endocytosis. The TfR can be targeted by direct interaction with conjugates of its ligand transferrin (Tf) or by monoclonal antibodies specific for the TfR. In this review we summarize the strategies of targeting the TfR in order to deliver therapeutic agents into tumor cells by receptor-mediated endocytosis.