ETV6 is a member of the ETS family of transcription factors. More than 40 translocations with ETV6 involvement have been reported in diverse types of hematological and non-hematological malignancies. The balanced chromosomal translocation t(12;21)(p13.2;q22.1), which leads to ETV6-RUNX1 fusion, represents the most frequent genetic rearrangement (19-27%) in initial childhood B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) and has been associated with good prognosis. The ETV6-NTRK3 gene fusion resulting from the t(12;15)(p13.2;q25) translocation was found to be characteristic for mammary analogue secretory carcinoma (MASC) of the salivary glands. Since MASC morphologically mimics other neoplasms, the detection of ETV6 rearrangements may be helpful for the differential diagnosis of MASC. In a subgroup of myeloproliferative disorders, the t(5;12)(q32;p13.2) translocation is a recurrent chromosome abnormality resulting in the fusion of ETV6 to the receptor tyrosine kinase PDGFRB. Patients carrying the t(5;12) translocation can be successfully treated with tyrosine kinase inhibitors.