1. The evidence for feedback regulation of neurotransmitter release by means of autoreceptors is questioned. 2. Autoreceptor function must meet the expectations for feedback loops. However, this concordance has not been observed in most neuroeffector systems. 3. The characteristics of per pulse transmitter release with changes in the parameters of stimulation in several autonomic systems do not support the ongoing operation of negative feedback loop mediated by locally released transmitter. Also, the effects of antagonists and agonists often do not comply with feedback expectations. 4. Evidence is provided that agonists and antagonists act at different loci to achieve their inhibiting and potentiating effects on transmitter release. 5. Future efforts should be directed to exploring the mechanism(s) of antagonist action and to a system-by-system analysis of the evidence for and against autoreceptor operation.