The interface between nanoscale electronic devices and biological systems enables interactions at length-scales natural to biology, maximizing communication between these two diverse yet complementary systems. Nanostructures and nanostructured substrates show enhanced coupling to artificial membranes, cells, and tissue. Such nano-bio interfaces offer better sensitivity and spatial resolution as compared to conventional planar structures. I will present the electrical properties of silicon nanowires (SiNWs) interfaced with embryonic chicken hearts and cultured cardiomyocytes. Utilizing the bottom-up approach enabled subcellular electrical recordings using the smallest reported device ever and thus exceeded the spatial and temporal resolution limits of other electrical recording techniques. I will discuss the synthetic breakthrough and novel fabrication required to realize the first new electronic measurement tool for intracellular measurements since patch-clamp of the 1970s – a truly three-dimensional nanoscale transistor. Finally, I will discuss my group’s current efforts to overcome the limits of cell-nanodevices interfaces. We are tackling these challenges through unique materials synthesis and device platform geometries. The exceptional synthetic control and flexible assembly of nanomaterials provides powerful tools for fundamental studies and applications in life science, and opens up the potential of merging active transistors with cells such that the distinction between nonliving and living systems is blurred.