Increasing studies have shown that the interactions between microRNAs (miRNAs) and environmental factors (EFs) play critical roles in determining phenotypes and diseases. In this study, we revealed a number of important biological insights by analyzing and modeling of miRNA-EF interactions and their relationships with human diseases. We demonstrated that the miRNA signatures of EFs could provide new information on EFs. More importantly, we quantitatively showed that the miRNA signatures of drug/radiation could be used as indicators for evaluating the results of cancer treatments. Finally, we developed a computational model that could efficiently identify the possible relationship between EF and human diseases. Meanwhile, we provided a website (http://cmbi.hsc.pku.edu.cn/miren) for the main results of this study. This study elucidates the mechanisms of EFs, presents a framework for predicting the results of cancer treatments, and develops a model that illustrates the relationships between EFs and human diseases.