The numerous biological applications of nanoparticles in general and nano-clays in particular are rooted in understanding and harnessing their dynamic nano-bio interface. Among clays, the intrinsically-mesoporous halloysite nanotubes (HNTs) have emerged in recent years as promising nanomaterials. The diverse interactions of these nanotubes with living cells, encompassing electrostatic, van der Waals, and ion exchange, along with cellular response, are crucial in determining the behaviour of HNTs in biological systems. Thus, rational engineering of the nanotube properties allows for vast applications ranging from bacteria encapsulation for bioremediation, through algae flocculation for aquaculture, to intracellular drug delivery. This review summarizes the many aspects of the nano-bio interface of HNTs with different cell types (bacteria, algae and fungi, and mammalian cells), highlighting biocompatibility/bio-adverse properties, interaction mechanisms, and the latest cutting-edge technologies.