A systematic characterization of the genetic alterations driving ALCLs has not been performed. By integrating massive sequencing strategies, we provide a comprehensive characterization of driver genetic alterations (somatic point mutations, copy number alterations, and gene fusions) in ALK− ALCLs. We identified activating mutations of JAK1 and/or STAT3 genes in ∼20% of 88 ALK− ALCLs and demonstrated that 38% of systemic ALK− ALCLs displayed double lesions. Recurrent chimeras combining a transcription factor (NFkB2 or NCOR2) with a tyrosine kinase (ROS1 or TYK2) were also discovered in WT JAK1/STAT3 ALK− ALCL. All these aberrations lead to the constitutive activation of the JAK/STAT3 pathway, which was proved oncogenic. Consistently, JAK/STAT3 pathway inhibition impaired cell growth in vitro and in vivo. Display omitted •Co-occurring somatic mutations of JAK1 and STAT3 promote oncogenesis•Novel chimera fuse transcription/repressor domains to tyrosine kinases (TKs)•Dual functional TK fusions are oncogenic and mediate STAT3 transformation•JAK/STAT3 inhibitors have therapeutic efficacy in pre-clinical ALCL models Crescenzo et al. provide a comprehensive characterization of driver genetic alterations in ALK− anaplastic large cell lymphomas (ALCLs) and uncover mechanisms leading to the constitutive activation of STAT3 in ALK− ALCL. JAK/STAT3 inhibitors have therapeutic efficacy in pre-clinical ALCL models.