Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase with critical roles in metabolism and neural development. Aberrant activation of ALK is a major oncogenic driver in several cancers, and has led to its intensive therapeutic targeting. Prior research has attempted to provide a mechanistic basis for the activation of ALK family receptors by their cognate cytokines, ALKAL1/2. However, as the current models are limited to the extracellular cytokine-binding domains of ALK and the related LTK, the field is quite far from a complete understanding of how ALK-cytokine assemblies gain their full signaling potential and what the role of other receptor domains is in that context. To address this paucity in our structural understanding of cytokine-mediated ALK activation, we aim to integrate advances in structure determination via electron microscopy and computational modeling. Here, we build upon innovative molecular tools to enable structure determination of complete ALK-cytokine assemblies via cryo-EM based on ALK-ligand complexes solubilised from membranes, and cryo-EM and cryo-ET on receptor-containing extracellular vesicles. By integrating full-length structures of ALK with molecular dynamics simulations, we will be able to contextualize and elucidate the structural events that lead to the activation of ALK. Collectively, our work will provide a complete structural and mechanistic blueprint for ALK activation to aid its interrogation in physiology and disease.