With their development in the past decade, molecular machines, which achieve specific tasks by responding to external stimuli, have gradually come to be regarded as powerful tools for a wide range of applications, rather than interesting molecular toys. This conceptual change in turn motivates scientists to design molecular machines with complex architectures. Due to the lack of general principles bridging the functions and the chemical structures of molecular machines, experience-based design becomes difficult with the increase of size and complexity of the architectures. Computer-aided molecular-machine design, therefore, has attracted widespread attention on account of its ability to model and investigate complex molecular architectures without too much time and expense required for synthetic experiments. Using leading-edge numerical-simulation techniques, the mechanisms underlying achieving tasks through response to external stimuli of a large number of existing molecular machines have been successfully explored. Based on the experience of studying existing molecular machines, generalized methodologies of predicting the properties and working principles of molecular candidates have been established, paving the way for de novo computer-aided design of molecular machines. In this perspective, we introduce cutting-edge techniques that have been applied for investigating and designing molecular machines. We show paradigms of computer-aided design of molecular machines, which can serve as guidelines for the investigation of new supramolecular architectures. Moreover, we discuss the limitations and possible future developments of current techniques and methodologies in the field of computer-aided design of molecular machines.