<p>Patients with estrogen receptor-positive (ER⁺) breast carcinoma often receive tamoxifen as an anti-estrogen therapy; however, a significant number still experience disease recurrence during treatment. The molecular mechanisms behind tamoxifen resistance are not yet fully understood. TAM mainly works by inhibiting estrogen receptor signaling pathways, inducing apoptosis, and causing growth arrest. Factors that influence TAM response include impaired bioactivation of tamoxifen and changes in the expression of tumor suppressor genes and proto-oncogenes, which are essential for regulating the cell cycle. Additionally, host factors, such as the processes involved in TAM bioactivation and drug transporters, play a crucial role in the therapeutic response. Understanding the interplay between tumor characteristics and host factors could provide valuable insights into TAM efficacy. Variations in gene expression associated with tamoxifen resistance may result from a combination of genetic mutations and epigenetic modifications. Clarifying the precise mechanisms of TAM response is crucial for improving treatment efficacy. Several therapeutic strategies have been explored to enhance TAM response, including drug replacement, epigenetic therapy, natural compounds, and innovative approaches like Antisense Oligonucleotides (ASOs). Combining these treatment modalities may improve patient survival more effectively than using tamoxifen alone.</p> Graphical Abstract <p></p>