The high affinity Nerve Growth Factor receptor TrkA is critical for the development, maturation and maintenance of central and peripheral nervous systems and plays an important role in immune system development and function. TrkA oncogenes exhibit spontaneous ligand-independent activity resulting from activating point mutation, deletion or somatic rearrangements leading to novel chimera formation and have been associated and implicated in several non-neural tumor types including carcinomas of the colon, thyroid and prostate, and acute myeloid leukemia. Despite the central role of TrkA in nervous system development, maturation and maintenance, there are no reports associating mutation-activated TrkA oncogenes with tumors of neural origin. The recent identification of the hypoxia-regulated alternative TrkAIII splice variant exhibiting constitutive oncogenic potential and expression in a subset of neural-crest derived tumors, has suggested an epigenetic mechanism, based upon alternative TrkA splicing, for regulating TrkA oncogenic/tumor promoting activity in tumors of neural origin. In this review, we focus on alternative TrkA splicing in cancer, through an examination of the structure, regulation of expression, potential modes and mechanisms of activation and activity of alternative TrkA splice variants.