Recent studies have demonstrated that in addition to biochemical and genetic interactions, cellular systems also respond to biophysical cues, such as electrical, thermal, and mechanical signals. However, we only have limited tools that can introduce localized physical stimuli and/or sense cellular responses with high spatiotemporal resolution. Inorganic semiconductors display a spectrum of physical properties and offer the possibility of numerous device applications. My group integrates material science with biophysics to study several semiconductor-based biointerfaces. In this talk, I will first pinpoint domains where semiconductor properties can be leveraged for biointerface studies, providing a sample of numbers in semiconductor-based biointerfaces. Next, I will present a few recent studies from our lab and highlight key biophysical mechanisms underlying the non-genetic optical modulation interfaces. In particular, I will present a biology-guided two-step design principle for establishing tight intra-, inter-, and extracellular silicon-based interfaces in which silicon and the biological targets have matched mechanical properties and efficient signal transduction. Finally, I will discuss new materials and biological targets that could catalyze future advances.