Startle is a fast response to sudden, intense stimuli and probably protects the organism from injury by a predator or by a blow. The acoustic startle response (ASR) of mammals is mediated by a relatively simple neuronal circuit located in the lower brainstem. Neurons of the caudal pontine reticular nucleus (PnC) are key elements of this primary ASR pathway. The ASR in humans and animals has a non-zero baseline, that is, the response magnitude can be increased or decreased by a variety of pathological conditions and experimental manipulations. Therefore, the ASR has been used as a behavioral tool to assess the neuronal basis of behavioral plasticity and to model neuropathological dysfunctions of sensorimotor information processing. Cross-species examples for the increase of the ASR magnitude are sensitization, fear-potentiation and drug-induced enhancement. Examples for the reduction of the ASR magnitude are habituation, prepulse inhibition, drug-induced inhibition and the attenuation by positive affect. This review describes the neuronal basis underlying the mediation of the ASR, as well as the neuronal and neurochemical substrates of different phenomena of enhancement and attenuation of the ASR. It also attempts to elucidate the biological background of these forms of behavioral plasticity. Special emphasis is put on the potential relevance of ASR modulations for the understanding of human psychiatric and neurological diseases.