Dogs (Canis lupus familiaris), derived from wolves (Canis lupus), are known as the first domesticated animal and dogs have been living in human environment for about 25.000 years. Today researchers tend to proclaim a self-domestication-process, but they are still figuring out, why and how this process started. During the Palaeolithic period, humans and wolves lived in similar structured family clans as cooperative hunters in the same ecological niche. Evolutionary continuity of mammalian brains enabled humans and wolves interspecific communication and social interaction which reduced stress and aggression during their frequently contacts as the first step of a natural domestication process. Domestication means decreased aggression and decreased flight distance concerning to humans. Therefore changes of the activity of the Hypothalamic-pituitary-adrenal (HPA) axis are suspected to be important during the domestication processes from wolf to dog. The hypothesis of Active Social Domestication (ASD) considers genetic selection as a necessary prediction but not a sufficient explanation of dog domestication. In addition dog domestication is suggested to be essentially an epigenetic based process that changes the interactions of the HPAaxis and the 5-Hydroxytryptamine (5-HT) system. The limbic brain regions such as hippocampus and amygdala play a key role in the mood control. They are sensitive to glucocorticoids and innerved by serotonergic projections. The HPAaxis and the 5-HT system are closely cross-regulated under physiological conditions. The activity of the HPAaxis is influenced thru an enhancement of the corpus amygdala and an inhibition thru the hippocampus. Hippocampal glucocorticoid receptor density (hGCR) is likely to affect its inhibitory effect on this system. Pro-social behaviour enhances epigenetically hGCR expression via increased serotonin and subsequently increased nerve growth factor levels binding on GRexon1;7promotorbloc inducing its demethylation and thus leading to decreased cortisol levels. Low cortisol levels increase social learning capability and promote the activity of the prefrontal cortex contributing to better executive function including better cognitive inhibition. Thus epigenetically decreased cortisol levels of less stressed human-associated wolf clans allowed them to extend their social skills to interactions with humans. Over time tame wolves could grow into domestic dogs able to emerge human directed behaviour.