Hebbian plasticity, as represented by long-term potentiation (LTP) and long-term depression (LTD) of synapses, has been the most influential hypothesis to account for encoding of memories. The evidence for the physiological relevance of LTP is indisputable. However, until recently the ways by which LTP physiologically is induced in its natural environment, the brain, was less clear. Nonetheless, current evidence points to neuromodulators as an indispensable element. The case for LTD in vivo is less certain. Even its relevance has been a matter of speculation and doubts. However, emerging evidence for a physiological role for LTD is promising, as the phenomenon has been observed at different brain regions. More needs to be done before LTD can claim an equal status alongside LTP.