This article argues that our intimate entanglement with digital technologies is challenging the foundations of current HCI research and practice. Our relationships to virtual realities, artificial intelligence, neuro-implants or pervasive, cyberphysical systems generate ontological uncertainties, epistemological diffusion and ethical conundrums that require us to consider evolving the current research paradigm. I look to post-humanism and relational ontologies to sketch what I call Entanglement HCI in response. I review selected theories—Actor-Network Theory, Post-Phenomenology, Object-Oriented Ontology, Agential Realism—and their existing influences on HCI literature. Against this background, I develop Entanglement HCI from the following four perspectives: (a) the performative relationship between humans and technology; (b) the re-framing of knowledge generation processes around phenomena; (c) the tracing of accountabilities, responsibilities and ethical encounters; and (d) the practices of design and mattering that move beyond user-centred design.