CDK4/6 inhibitor sequencing after adjuvant exposure presents complex decision-making challenges without robust supporting data. When patients experience progression following adjuvant CDK4/6 inhibitor therapy, the benefit of rechallenging with the same class in the metastatic setting remains uncertain. Clinical practice often involves switching between CDK4/6 inhibitors, such as moving from adjuvant abemaciclib to metastatic ribociclib, based on limited data from metastatic studies showing some benefit from continued CDK4/6 inhibition despite progression. This knowledge gap highlights the need for novel targeted therapies, including CAT6 inhibitors, CDK2 inhibitors, and specific PI3K inhibitors, for patients with prior CDK4/6 exposure. Future research must address optimal sequencing strategies and identify predictive biomarkers to guide treatment selection for patients with CDK4/6 inhibitor–resistant disease.