Balanced modulation of multiple targets is an attractive therapeutic strategy in treating complex diseases including cancer. Comparing with drugs combination, single molecule modulating desirable multiple targets has advantages in pharmacokinetic and pharmacodynamics. Different from previous reviews, we provided an overview of reported multitarget antitumor agents from the viewpoint of pharmacophores. These multitarget antitumor agents were designed by combination of pharmacophores or by high-throughput screening plus structural modification, which were exemplified by the privileged pharmacophore quinazoline and several other popular pharmacophores, including phenylaminopyrimidine, anthracycline and naphthalimide. Previous research demonstrated the importance of in-depth validation against multiple targets not only in cell-free system, but also in cancer cells. Furthermore, the multitarget compounds were also effective for resistance cell lines which highlighted their antitumor potency in the era of increasing drug resistance in cancer patients.