HOX transcript antisense intergenic RNA (HOTAIR) is an oncogenic non-coding RNA whose expression is strongly correlated with the tumor grade and prognosis of a variety of carcinomas including breast cancer (BC). HOTAIR regulates various target genes via sponging and epigenetic mechanisms and controls various oncogenic cellular and signaling mechanisms including metastasis and drug resistance. In BC cells, HOTAIR expression is regulated by a variety of transcriptional and epigenetic mechanisms. In this review, we describe the regulatory mechanisms that govern HOTAIR expression during cancer development and explore how HOTAIR drives BC development, metastasis, and drug resistance.