Uncontrolled cellular proliferation, mediated by dysregulation of the cell-cycle 
machinery and activation of cyclin-dependent kinases (CDKs) to promote 
cell-cycle progression, lies at the heart of cancer as a pathological process. 
Clinical implementation of first-generation, nonselective CDK inhibitors, 
designed to inhibit this proliferation, was originally hampered by the high risk 
of toxicity and lack of efficacy noted with these agents. The emergence of a new 
generation of selective CDK4/6 inhibitors, including ribociclib, abemaciclib and 
palbociclib, has enabled tumour types in which CDK4/6 has a pivotal role in the 
G1-to-S-phase cell-cycle transition to be targeted with improved effectiveness, 
and fewer adverse effects. Results of pivotal phase III trials investigating 
palbociclib in patients with advanced-stage oestrogen receptor (ER)-positive 
breast cancer have demonstrated a substantial improvement in progression-free 
survival, with a well-tolerated toxicity profile. Mechanisms of acquired 
resistance to CDK4/6 inhibitors are beginning to emerge that, although 
unwelcome, might enable rational post-CDK4/6 inhibitor therapeutic strategies to 
be identified. Extending the use of CDK4/6 inhibitors beyond ER-positive breast 
cancer is challenging, and will likely require biomarkers that are predictive of 
a response, and the use of combination therapies in order to optimize CDK4/6 
targeting.