Objective: Histamine (HA) and hypocretin/orexin (OX) neurons in the posterior hypothalamus interact with each other and project widely throughout the almost entire nervous system to control complex brain and body functions. Methods: Combined electrophysiological, pharmacological, and molecular genetic (knockout- mice) approaches were used to investigate the effects of HA and OX on neuronal excitability and synaptic transmission in the hippocampus of rats and mice in vitro. Results: HA and OX evoke synchronous sharp wave and theta rhythm-related network activity, which promotes induction of pathway-specific and enduring forms of long-term synaptic plasticity that require (i) activation of multiple protein kinases (CaMKII, PKA, PKC, MAPK, TrK), (ii) protein synthesis, and (iii) Per1 clock gene- dependent transcriptional control. Conclusion: Our data indicate a mechanistic and molecular convergence of HA and OX signaling in the control of network activity, long-term synaptic plasticity, and clock gene dynamics beyond circadian control that may be important for the understanding of behavioral and cognitive-mnemonic states, both in health and disease.