INTRODUCTION: Hormone receptor-positive (HR+), HER2-negative metastatic breast cancer (mBC) remains a prevalent and challenging disease. Endocrine therapy (ET) combined with CDK4/6 inhibitors is the first-line standard of care, yet resistance mechanisms, including ESR1 mutations, drive disease progression. Novel oral selective estrogen receptor degraders (SERDs) have emerged as promising therapeutic agents after progression with CDK4/6 inhibitors secondary to ESR1 mutations. However, the available studies on SERDs differ in design, study population, and outcomes, necessitating a critical review of available data. AREAS COVERED: This review explores the mechanisms, clinical efficacy, and safety profiles of oral SERDs in HR-positive, HER2-negative mBC, particularly following progression on CDK4/6 inhibitors. Recent key clinical trials, including EMERALD, SERENA-2, EMBER-3 and AMEERA-3, are analyzed, highlighting their efficacy in overcoming resistance, especially in ESR1-mutant populations. EXPERT OPINION: Oral SERDs offer enhanced bioavailability and convenience compared to fulvestrant, representing a critical advancement in endocrine therapy. Their integration into treatment strategies, particularly in combination regimens and ctDNA-driven approaches, may improve patient outcomes and address resistance mechanisms. However, other than ESR1 mutations, clinical refinement for patient selection is limited. Further trials are needed to optimize patient selection for oral SERD use and define the most effective combination strategies with oral SERDs.