Electrical block of neural conduction has myriad potential clinical applications including treatment of pain and autonomic dysfunction such as heart failure, diabetes and inflammation. However, these therapeutic targets require block of small diameter myelinated Ad- and B-fibers and unmyelinated C-fibers, while the majority of prior studies of block were on block of large diameter myelinated Aa-fibers. The continued development of nerve block and its clinical translation are limited by: (1) the high energy required for conduction block, especially for the small diameter nerve fibers most relevant for bioelectronic therapies, (2) the strong excitatory response that occurs at the onset of blocking signals, which is likely to be exacerbated by the high block thresholds of small diameter axons, and (3) the lack of control over which specific nerve fibers are blocked, such that blocking small diameter axons also results in block of larger diameter axons. We propose rigorous engineering design to optimize the performance of nerve block waveforms and electrodes and in vivo testing of their performance in both small and large animals. Aim 1 is to optimize simultaneously the waveform and electrode geometry to meet each of three distinct performance criteria: minimize energy required for block, minimize onset response associated with the initiation of block, and enable selective block of small diameter axons (myelinated Ad- or B- fibers or unmyelinated C-fibers) while preserving conduction in large diameter Aa-fibers. We will combine validated computational models with engineering optimization via a particle swarm algorithm to design new waveform shapes and electrode geometries to achieve our performance metrics and thereby greatly increase the utility of nerve conduction block. In Aim 2, we will measure the responses of different types of nerve fibers (A-, B-, and C-fibers) in both the vagus nerve and the sciatic nerve of anesthetized rats to compare the performance of optimized block waveforms and electrode geometries to conventional waveform shapes (sinusoids, rectangular pulses) and electrode geometries (bipolar, tripolar) used for block of nerve fiber conduction. In Aim 3 we will measure both nerve fiber responses and physiological responses, including electromyograms and changes in heart rate, to block of the pig vagus nerve to quantify performance, including energy, onset response, and selectivity, in a large, multi-fascicular nerve that represents well human nerves. The outcomes will be novel waveforms and electrode geometries that overcome the performance limitations of current approaches to conduction block including the high energy requirements, the strong excitatory onset response, and the lack of control over which specific nerve fibers are blocked. These enhanced capabilities will advance electrical nerve block as an experimental tool and provide technologies to enable the continued translation of new bioelectronic therapies.