#Hee-Jin Kim and Chul Won Choi contributed equally to this work. Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are collectively called “Philadelphia-negative classical myeloproliferative neoplasms” (MPNs), and the discovery of the JAK2V617F mutation in 2004 led us to make new progress in the diagnostic approach and therapeutic strategy for MPNs. Thereafter, other clonal markers, such as mutations of the MPL or CALR genes, were discovered and listed as useful markers for the distinction of MPN from reactive myeloproliferation. The identification of recurrent gain-of-function somatic mutations in the JAK2 and MPL genes during the years 2005–2007 provided critical insights into non-BCR/ABL1 MPNs that have advanced our understanding of the molecular pathophysiology of these diseases. The JAK2 and MPL mutations were readily incorporated into the diagnostic criteria for PV, ET, and PMF in the 2008 World Health Organization (WHO) classification [1]. Thereafter, the growing application of high-throughput sequencing technologies to the identification of genetic alterations at the nucleotide level has revealed a long list of genes, other than JAK2 and MPL, which are mutated in MPNs. It is expected that 2 of these genes, CALR and CSF3R, will be added to the upcoming WHO classification, based on their significant frequency of occurrence and genotype-phenotype correlation, particularly in terms of therapeutic and prognostic implications [2]. The CALR gene will appear in the diagnostic criteria for ET and PMF; CALR mutations are reported to be detected in ∼70% of JAK2-nonmutated ET and ∼85% of JAK2-nonmutated PMF. CALR encodes the protein calreticulin, which has multiple functions and plays roles in, for example, cell proliferation and apoptosis. CALR mutations occur exclusively in exon 9 (the last exon) and are most commonly small deletions or insertions, with or without substitutions. The two most common mutations that account for ∼80% of all CALR mutations, c.1092_1143del (p.L367fs*46) and c.1154_1155insTTGTC (p.K385fs*47), have been designated as type 1 and 2, respectively. The mutations both result in a frameshift to an alternative reading frame and generate a novel amino acid sequence at the C-terminus of the protein. Clinically, compared to patients with JAK2 mutations, patients with CALR mutations have a higher platelet count, lower Hb and leukocyte levels, a lower risk of thrombosis, and a more indolent disease course [3]. Interestingly, mutation type was found to be associated with disease subtype (predilection for type 1 mutations in PMF) and with the clinical course of the disease (shorter survival with type 2 mutations in PMF) [4]. Technically, PCR and amplicon-sizing analyses can detect CALR mutations with high sensitivity and provide quantitative information, and direct sequencing analysis can then fully characterize the mutations. Of note, the 3 major driver mutations in non-BCR/ABL1 MPNs, JAK2, MPL, and CALR, occur in an almost mutually