The serotonin receptor subtype 5-HT1A was one of the first serotonin receptor subtypes pharmacologically characterized. Over the last twenty years the 5-HT1A receptor has been the object of intense research efforts as witnessed by the 5-HT1A acting drugs marketed as anxiolytics. In recent years, several new chemical entities targeting the 5-HT1A receptor (alone or in combination with other molecular targets) have been proposed for novel therapeutic indications (neuroprotection, cognitive impairment, Parkinson Disease and related disorders, pain treatment). The present review will focus on those 5-HT1A receptor agents that entered preclinical trials starting from 2000.