Immune system regulates homeostasis of the body during normal and pathological condition where macrophages play very important role. They can be polarized in two phenotypes, either M1 or M2 type, depending on the stimuli present in their microenvironment. In cancer conditions, increased infiltration of leukocyte occurs where macrophages dominate and they promote its growth and are known as tumor–associated macrophages (TAMs). These TAMs resemble with M2 type. For cancer treatment, either infiltration of macrophages at tumor site or repolarization of TAMs towards M1type can be targeted. Biological Response Modifiers (BRMs) are potential immuno–modulators that can be used for targeting TAMs. Melatonin could be used as a BRM as it shows the immuno–modulatory property via affecting different players of immune system. In this review, we summarize properties of TAMs and their role in tumor growth and progression and how they can be targeted for cancer treatment using melatonin as BRM.