The management of estrogen receptor-positive (ER+) breast cancer has undergone a significant transformation over the past decade, thanks to the development of mechanistically-based combinations with CDK4/6 inhibitors (CDK4/6i) aimed at delaying antiestrogen resistance. Despite the substantial improvements in patient outcomes, those treated with CDK4/6i combinations still face high rates of disease progression. In this talk, I will explore the genomic basis of therapeutic resistance to CDK4/6i, utilizing tumor sequencing and liquid biopsy.