Cancer has become a serious concern in public health. Harmful side effects and multidrug resistance of traditional chemotherapy have prompted urgent needs for novel anticancer drugs or therapeutic approaches. Anticancer peptides (ACPs) have become promising molecules for novel anticancer agents because of their unique mechanism and several extraordinary properties. Most α-helical ACPs target the cell membrane, and interactions between ACPs and cell membrane components are believed to be the key factor in the selective killing of cancer cells. In this review, we focus on the exploitation of the structure and function of α-helical ACPs, including the distinction between cancer and normal cells, the proposed anticancer mechanisms, and the influence of physicochemical parameters of α-helical ACPs on the biological activities and selectivity against cancer cells. In addition, the design and modification methods to optimize the cell selectivity of α-helical ACPs are considered. Furthermore, the suitability of ACPs as cancer therapeutics is discussed.