Inflammatory myofibroblastic tumors (IMT) are mesenchymal solid tumors that occur preferentially in children and young adults. They present as myofibroblastic cell proliferations accompanied by plasmocytes and lymphocytes. Recent cytogenetic and molecular observations showed non-random abnormalities of chromosomal band 2p23 resulting in a rearrangement of the ALK gene. This finding of a specific gene alteration suggests a neoplastic rather than a reactive inflammatory process for IMT tumorigenesis. ALK is a tyrosine kinase oncogene initially found to be rearranged in anaplastic large-cell lymphomas (ALCL). Of note, the breakpoints within ALK, and also within some of the ALK fusion gene partners, such as TPM3 or CLTC, are similar in IMT and ALCL. The consistent involvement of ALK, together with the diversity of partner genes, underlines the central role of ALK constitutive activation in IMT development, as well as the importance of homodimerization mechanisms of the chimeric fusion proteins in this activation. Immunohistochemical analyses performed on paraffin embedded tissue sections have shown positive ALK expression with cytoplasmic localization in half of the IMT cases containing the molecular ALK rearrangement. In conclusion, these novel molecular data have defined a group of IMT of neoplastic origin characterized by the presence of ALK alterations. The description of ALK gene rearrangements in IMT and ALCL is the second example, after the observation of ETV6-NTRK3 in congenital fibrosarcoma and in a case of chronic myeloid leukemia, of identical gene fusions occurring in two different cell lines: hematopoietic and mesenchymal. The search for rearrangement of ALK by fluorescence in situ hybridization (FISH) is a useful complementary tool for IMT diagnosis.