Homeostatic mechanisms control food intake and body weight. The central and peripheral pathways that are involved are well known. Short term food intake is mainly regulated by factors from the gastrointestinal tract such as ghrelin and CCK. Long term maintenance of body weight is based on the amount of fat in the body, reflected by plasma leptin and brain insulin concentrations. The highest and lowest acceptable levels for these homeostatic regulatory mechanisms are determined by our genes. Unfortunately, the thrifty gene defines the highest acceptable level at a too high level, which implies that overweight and moderate obesity will not be counteracted by homeostatic regulatory mechanisms (and related pharmacological treatments). It is argued that research (and treatment) in the field of overeating and obesity should therefore focus on so-called non-homeostatic mechanisms: palatability, taste, reward and hedonics (the second best thing in life). In neuroendocrinological terms this puts the emphasis on brain areas such as the lateral hypothalamus and the mesolimbic dopamine system and neurotransmitters such as melanin concentrating hormone (MCH) and the endocannabinoids.