Inflammatory myofibroblastic tumors (IMTs) are soft tissue neoplasms with rare metastatic potential. Approximately half of IMTs are positive for an ALK rearrangement, and ALK inhibitors have been used successfully in the treatment of IMTs with a variety of ALK fusions. This report describes a 21-year-old woman with an aggressive, metastatic IMT with a novel NUMA1-ALK fusion that showed a dramatic response to the ALK inhibitors crizotinib and alectinib. To our knowledge, this report provides the first published description of an IMT with a NUMA1-ALK fusion. The patient's aggressive IMT responded favorably to crizotinib and alectinib, suggesting that ALK inhibitors may be effective in IMT with NUMA1-ALK fusions. We review published reports of ALK-driven IMTs that have received ALK inhibitor therapy and suggest characteristics that may be associated with favorable response to treatment. We also discuss the strengths and limitations of immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing in the diagnosis and management of IMTs.