Hormone receptor positive (HR+) breast cancer constitute the largest subtype of breast cancers. With the advent of new high throughput research technologies, there has been a profound acceleration in the identification and understanding of resistance mechanisms to endocrine therapies. The landscape of treatment options for HR+ breast cancers have changed dramatically in the last 5 years with the introduction of molecular targeted therapies such as CDK4/6 inhibitors, and as a result, changing the natural history of this breast cancer subtype. New treatment algorithms of combination therapies that are more complex than ever before have emerged, and so has the emergence of new patterns of treatment resistance.The strategies to combat these cancers resistant to combination therapies are not yet defined, and represent the next major clinical challenge in HR+ breast cancer. I will discuss new treatment strategies, how the molecular landscape of endocrine therapy resistance may affect the response to CDK4/6 inhibitors, and novel strategies that are required to overcome the next wave of treatment resistance in HR+ breast cancer.