Abstract Cyclin-dependent kinase (CDK) 4/6 inhibitors have transformed the treatment landscape of patients with hormone receptor–positive breast cancers. However, despite improvements in clinical outcomes, the approximately 70% of patients with tumors that are not intrinsically resistant to a CDK4/6 inhibitor still ultimately acquire resistance, which leads to a dilemma for clinicians when deciding which treatment to offer patients when they demonstrate disease progression on a CDK4/6 inhibitor. As such, many groups have sought to understand the mechanisms of resistance to CDK4/6 inhibitors, mostly focusing on genetic alterations associated with resistance. Though several recurrent mutations have been described, they are not consistent enough to guide clinical practice or generate novel rational treatment options. Two recent publications have used transcriptomic analysis to unravel distinct mechanisms driving resistance to individual CDK4/6 inhibitors and in doing so have identified biomarkers that could potentially help identify the next course of treatment for patients following disease progression.