The interferons (IFNs) are an endogenous pleiotropic family of cytokines that perform fundamental physiological functions as well as protecting host organisms from disease and in maintaining homeostasis. This review covers the effects of endogenous IFN on the nervous system. It starts with the description of its receptors, followed how it modulate neuronal activity, mood, sleep, temperature, the endocrine system, the opioid system and how it regulate food consumption and the immune system. Similar to other multifunctional cytokines, an excessive or inappropriate activity of IFNs can cause toxicity and even death. Furthermore, IFNs are currently the major treatment modality for several malignant and non-malignant diseases such as chronic hepatitis C and B, multiple sclerosis, hematological malignancies, malignant melanoma, renal cell carcinoma, etc.