Designing drugs that can simultaneously interact with multiple targets is a promising approach for treating complicated diseases. Compared to using combinations of single target drugs, multitarget drugs have advantages of higher efficacy, improved safety profile, and simpler administration. Many in silico methods have been developed to approach different aspects of this polypharmacology-guided drug design, particularly for drug repurposing and multitarget drug design. In this review, we summarize recent progress in computational multitarget drug design and discuss their advantages and limitations. Perspectives for future drug development will also be discussed.