Accumulated empirical clinical experience, supported by animal or cell line models, has initiated efforts of predicting synergistic combinatorial drugs with more-than-additive effect compared with the sum of the individual agents. Aiming to construct better computational models, this review started from the latest updated data resources of combinatorial drugs, then summarized the reported mechanism of the known synergistic combinations from aspects of drug molecular and pharmacological patterns, target network properties and compound functional annotation. Based on above, we focused on the main in silico strategies recently published, covering methods of molecular modeling, mathematical simulation, optimization of combinatorial targets and pattern-based statistical/learning model. Future thoughts are also discussed related to the role of natural compounds, drug combination with immunotherapy and management of adverse effects. Overall, with particular emphasis on mechanism of action of drug synergy, this review may serve as a rapid reference to design improved models for combinational drugs.