This chapter presents our findings that challenge the conventional view—that negative pulses are more effective than positive pulses in extracellular stimulations. During sustained high-frequency stimulations (HFS) with alternating monophasic pulses of opposite polarities, the firing induced by positive pulses became comparable to that induced by negative pulses. Furthermore, the two types of pulses activated different subpopulations of neurons. For neurons that responded to both types of pulses at baseline, positive pulses actually surpassed negative pulses during HFS. Our computational simulations revealed complex interactions between the two pulse types in their activation mechanisms on axonal membrane.