The histamine H3 receptor (H3R), belonging to the family of G-protein-coupled receptors, is predominantly expressed in the central nervous system (CNS). Since its discovery by Arrang et al., it was related to several central nervous system diseases by playing a key role as actuator of neurotransmitter release for, e.g., dopamine, acetylcholine, noradrenaline, or serotonin. Therefore, a huge number of H3R antagonists have been investigated on their potential therapeutic applicability in obesity, depression, mood disorders, neuropathic pain, and sleep– wake disorders (including narcolepsy) as well as cognitive and CNS-linked sensorimotor deficit disorders such as Parkinson’s disease, attention deficit hyperactivity disorder, Alzheimer’s disease, schizophrenia, alcohol addiction, energy homeostasis, epilepsy, obstructive sleep apnea, diabetic neuropathic pain, Tourette’s syndrome, and catalepsy. So far, many structurally diverse H3R antagonists have been synthesized and pharmacologically evaluated. Despite a high diversity of compounds, these structures share a similar construction pattern. The pharmacophore contains a tertiary basic amine (postulated to interact with the conserved aspartate 114 in helix 3), a linker (commonly a linear propyloxy chain or structurally constrained), a central core, and “the eastern” arbitrary region (with high diversity such as second basic, acidic, lipophilic, or polar moieties of different sizes).