Progesterone (Pg) is a pregnancy-related hormone that prepares the endometrium for the implantation of the fertilized zygote and suppresses myometrial contractility for the maintenance of pregnancy. At high concentrations, it acts as a natural immunosuppressant avoiding the rejection of a half allogeneic foetus. It is the precursor of many other related steroid hormones, but what is its role in the human breast? In this chapter, we will discuss some aspects related to Pg and its role in breast development and in the neoplastic disease. Understanding the mechanisms related to Pg-induced effects in the normal and neoplastic mammary gland will light the way to exploit this hormone signalling pathway therapeutically. We will introduce some aspects of the effects of progestins in normal breast development, breast cancer risk and in neoplastic growth, and we will describe ongoing clinical trials in breast cancer using progestins or antiprogestins.