Antiestrogen therapies have been a staple treatment option for estrogen receptor (ER)-positive breast cancer patients for many decades, but resistance remains a major obstacle for continued successful treatment. In this chapter, we will discuss the preclinical and clinical research advancement in the development of novel strategies to overcome breast cancer endocrine resistance. We will focus on the current successes and emerging future developments in targeting growth signaling pathways (i.e., CDK4/6, PI3K/AKT/mTOR, and IGF-1) and ER cofactors such as SRC family cofactors and Mediator Subunit 1 (MED1) using small molecules, antibodies, and RNA nanotechnology. We will also provide future perspective for other potential novel therapeutic targets such as epigenetic modification, noncoding RNAs, immunotherapy, etc. and the expansion of therapeutic options in endocrine-resistant breast cancers.