Aldo-keto reductases (AKRs) are a superfamily of promiscuous enzymes that have been chiseled by evolution to act as catalysts for numerous regulatory pathways in humans. However, they have not lost their promiscuity in the process, essentially making them a double-edged sword. The superfamily is involved in multiple metabolic pathways and are linked to chronic diseases such as cataracts, diabetes, and various cancers. Unlike other detoxifying enzymes such as cytochrome P450s (CYP450s), short-chain dehydrogenases (SDRs), and medium-chain dehydrogenases (MDRs), that participate in essential pathways, AKRs are more widely distributed and have members with interchangeable functions. Moreover, their promiscuity is ubiquitous across all species and participates in the resistance of pathogenic microbes. Moreover, the introduction of synthetic substrates, such as synthetic molecules and processed foods, results in unwanted "toxification" due to enzyme promiscuity, leading to chronic diseases.