A recent article published in Advances in Experimental Medicine and Biology reported that sulfonation and desulfation are two opposing processes that represent an important layer of regulation of estrogenic activity through ligand supplies. The article elaborated that enzymatic activities of families of enzymes, known as sulfotransferases and sulfatases cause structural and functional changes of the steroids, thyroids, xenobiotics, and neurotransmitters. It was stated that estrogen sulfotransferase (EST) and steroid sulfatase (STS) represent negative and positive regulation of the estrogen activity, respectively; because EST-mediated sulfation deactivates estrogens, whereas STS-mediated desulfation converts the inactive estrogen sulfates to active estrogens. Additionally, regulation of estrogens and other signal molecules especially at the local tissue levels has gained increased attention in the context of metabolic disease recently. EST expression is detectable in the subcutaneous adipose tissue in both obese women and men, and the expression of EST is markedly induced in the livers of rodent models of obesity and type-2 diabetes. STS was found to be upregulated in patients with chronic inflammatory liver diseases. Remarkably, the tissue distribution and the transcriptional regulation of EST and STS exhibit obvious sex and species specificity. On the other hand, EST ablation produces completely opposite metabolic phenotype in female and male obese mice. Meanwhile, adipogenesis is also differentially regulated by EST in murine and human adipocytes.