Actively replicating RNA viruses in nature are continually changing their genetic information by spontaneous mutations. These changes often result in alterations in immune-sensitivity, drug-sensitivity, cell-tropism, and host-range, causing uncontrollability of the pathogen and emerging/re-emerging infections. To better understand the virus changes and develop effective methods to control the moving targets, it is essential to obtain information on changes in viral genomes and proteins. Although information on genetic changes is being accumulated very rapidly, assessment of changes in protein structure and function still requires time-consuming works. In this review, we will overview mutation studies of human immunodeficiency virus and other RNA viruses. In addition, we will introduce recent advances in the computational science and its application on mutation studies and drug development.