The prospective use of upcoming nanometer CMOS technology nodes (65nm, 45nm, and beyond) in bio-electronic interfaces is raising a number of important issues concerning circuit architectures and design. In particular, the advantages of scaling and higher density integration must be balanced against the requirements of low noise design, uniform power density and surface temperature distribution, better component matching, and immunity to parameter variations. Dealing with these constraints also requires more innovative approaches towards hybrid integration technologies. In this paper, we discuss the key design issues with specific examples from DNA detection, protein detection, and neuro-electronic interfaces.