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Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (h channels) form the molecular basis for the hyperpolarization-activated current, I_h, and modulation of h channels contributes to changes in cellular properties critical for normal functions in the mammalian brain and heart. Numerous mechanisms underlie h channel modulation during both physiological and pathological conditions, leading to distinct changes in gating, kinetics, surface expression, channel conductance or subunit composition of h channels. Here we provide a focused review examining mechanisms of h channel regulation, with an emphasis on recent findings regarding interacting proteins such as TRIP8b. This review is intended to serve as a comprehensive resource for physiologists to provide potential molecular mechanisms underlying functionally important changes in I_h in different biological models, as well as for molecular …