Endocrine therapy (ET) constitutes the usual first-line of therapy for patients in the treatment of metastatic hormone receptor-positive breast cancer. Unfortunately, not all patients respond to first-line endocrine treatment due to intrinsic resistance, while others may initially respond but eventually progress with secondary acquired resistance leading to disease progression. Mechanisms of resistance to anti-estrogen therapy include, loss of expression for estrogen or progesterone receptor, upregulation of epidermal receptor growth factor 2, increased receptor tyrosine kinase signaling, leading to activation of various intracellular pathways that are involved in signal transduction such as PI3K/AKT/mammalian target of rapamycin, and others. Growing understanding of the signal cascade of estrogen receptors and the signaling pathways that interact with estrogen receptors has revealed the complex role of these receptors in cell growth and proliferation, and on the mechanism in development of resistance. These insights have led to the development of targeted therapies that may prove to be effective options for the treatment of breast cancer and may overcome hormone therapy resistance. In this review we summarize some of the mechanisms of endocrine resistance, selected clinical trials of ET and targeted therapies, which might interfere with estrogen receptor pathways and might reduce or reverse resistance to traditional, sequential, single-agent ET.