Multi-target drugs can simultaneously adjust multiple links of the disease network. Despite the higher efficacy and lower toxicity caused by single targets, multi-target drugs become ideal drugs for treating complicated diseases as well the main direction of drug R & D. By virtue of their structural diversity, higher multi-target activity and lower toxicity, natural products become an important source for developing multi-target drugs. Computer-aided drug design (CADD) is a commonly used multi-target drug R&D method, which mainly includes virtual screening and pharmacophore design. In this paper, the authors made a systematical analysis and discussed the prospects and advantages of various methods for multi-target drug R&D with natural products.