ALDH1A1, one important member of 19 ALDHs, can metabolize reactive aldehydes to their corresponding carboxylic acid derivatives and play important physiological and toxicological roles in many areas, including CNS, metabolic disorders, and cancers. Overexpression of ALDH1A1 correlates with poor prognosis and tumor aggressiveness, is associated with drug resistance in traditional chemotherapy for cancer treatment and contributes to obesity, diabetes, and inflammation. So, inhibition of ALDH1A1 may offer new therapeutic options for patients with cancer, obesity, diabetes, and inflammation. Up to now, many ALDH1A1 inhibitors with different scaffolds have been identified and developed as useful chemical tools for better understanding of the functions of ALDH1A1 in physiologic and pathophysiologic conditions. In this review, the advances in the discovery and development of selective ALDH1A1 inhibitors are summarized, and opportunities and challenges associated with this field are also discussed.