Estrogen has an important role in regulation of fat metabolism. Recent studies indicated that this process occurred due to inhibition of lipolysis by external estrogen administration. However, there was limited information regarding molecular process responsible for this phenomenon. This paper was aimed to present a brief update on recent studies explaining the effect of estrogen on adipose tissue lipolysis and the molecular pathway involved in this process. It is suggested that the effect of estrogen to reduction of lipolysis was through activation of estrogen receptor alpha (ER-α) in adipose tissue. This finding is supported by the fact that mice lacking of ESR1 gene (encodes ER-α) accumulate more fat and ESR1 mRNA in human adipose tissue was inversely correlated with body mass index (BMI). Future study should be aimed to clarify the role of ER-α on lipolysis in adipose tissue during weight loss intervention. Additionally, new pharmacological or nutritional treatment with ability to modulate ER-α activity/expression could be used as a potential weight loss intervention.