As a new class of synthetic receptors, molecularly imprinted polymers (MIPs) have shown great potential in many applications because of their good specific recognition ability, high stability, and easy preparation. The ultimate goal of molecular imprinting is to obtain MIPs that can be routinely used as alternatives to natural antibodies and receptors. However, the presently developed MIPs targeting small organic molecules mostly fail to show specific bindings in aqueous solutions, which is in sharp contrast to biological receptors and significantly limits their practical applications in such areas as biomimetic assays and sensors. Many efforts have been devoted to address this issue in the past two decades. In this feature article, I provide a detailed overview of the progress made in the development of water-compatible MIPs with an emphasis on our strategies to solve this challenging problem. Moreover, some still existing challenges and future prospects in this research area are also presented. (C) 2014 Elsevier Ltd. All rights reserved.