AbstractA series of aldehydes of varying protein crosslinking strengths have been tested on intact and internally perfused crayfish axons. Non‐crosslinking aldehydes have no effect, or cause a gradual decline in resting potential and overshoot with no widening of the spike. Strong crosslinking compounds, such as acrolein, crotonaldehyde, and glutaraldehyde, widen the action potential significantly while reducing its amplitude. Differences in the shapes of the resulting action potentials and accompanying impedance changes suggest that each crosslinking aldehyde exerts different effects on the axon. Glutaraldehyde, the strongest crosslinking agent tested, slows both rising and falling phases of the spike, and also of the impedance change, suggesting a prolongation of the transient increase in sodium conductance. The ability of protein crosslinking agents to alter excitability, and particularly to slow the various phases of the action potential, provides support for the hypothesis that a conformational change in a protein or protein‐phospholipid complex is involved in excitation.