Boron-doped silicon nanowires (SiNWs) were used to create highly sensitive, real-time electrically based sensors for biological and chemical species. Amine- and oxide-functionalized SiNWs exhibit pH-dependent conductance that was linear over a large dynamic range and could be understood in terms of the change in surface charge during protonation and deprotonation. Biotin-modified SiNWs were used to detect streptavidin down to at least a picomolar concentration range. In addition, antigen-functionalized SiNWs show reversible antibody binding and concentration-dependent detection in real time. Lastly, detection of the reversible binding of the metabolic indicator Ca2+ was demonstrated. The small size and capability of these semiconductor nanowires for sensitive, label-free, real-time detection of a wide range of chemical and biological species could be exploited in array-based screening and in vivo diagnostics.