Recurrent mutations in calreticulin (CALR) are present in approximately 20% of patients with myeloproliferative neoplasms (MPN). Since its discovery in 2013, we now have a more precise understanding of how mutant CALR, an endoplasmic reticulum chaperone protein, activates the JAK/STAT signaling pathway via a pathogenic binding interaction with the thrombopoietin receptor, MPL, to induce MPN. In this Spotlight, we review the current understanding of the biology underpinning mutant CALR driven MPN, discuss clinical implications, and highlight future therapeutic approaches.