ALK encodes a transmembrane receptor tyrosine kinase. This gene exerts characteristic oncogenic activities through fusion to several gene partners or mutations both in hemato-poietic and non-hematopoietic solid tumors. Translocations affecting the ALK gene locus are frequently found in anaplastic large cell lymphoma (ALCL), an aggressive non-Hodgkin lymphoma arising from T-cells. The most frequent translocation t(2;5) results in a fusion with the NPM1 (nucleophosmin a.k.a. nucleolar phosphoprotein B23, numatrin) gene located on chromosome 5q35. This rearrangement results in a NPM1/ALK fusion protein, which is constitutively activated through autophosphorylation, and that in turn mediates malignant cell transformation by activating downstream effectors like e.g. STAT3. Additionally, inversions affecting the ALK gene located on the short arm of chromosome 2 [inv(2)(p21p23)] have been frequently detected in non-small cell lung cancer (NSCLC) and lead to the formation of EML4-ALK fusion transcripts. ALK kinase targeted therapies may represent a very effective therapeutic strategy in NSCLC patients carrying EML4-ALK rearrangements.