Despite the significant progress in anticancer drug development over recent years, there is a vital need for newer agents with unique, but still effective, mechanisms of action in order to treat the disease, particularly the highly aggressive and drug-resistant types. Alkylating agents, in particular nitrogen-based alkylators, are commonly used to treat hematological and solid malignancies; they exert their antineoplastic effects at all phases of the cell cycle and prevent reproduction of tumor cells. Certain alkylating agents have been designed to be more lipophilic, enabling the compound to penetrate the cell and enhance its alkylating activity against tumors. This review details the evolution of currently available alkylating agents and their profiles, with a focus on nitrogen-based alkylating agents, as important anticancer therapy strategies.