The control of calcium signaling between plasma membrane dihydropyridine receptors (DHPRs or L-type calcium channels) and ryanodine receptors (RyRs or calcium release channels) located in the endoplasmic/sarcoplasmic reticulum (ER/SR) underlies a broad array of functions including skeletal muscle contraction, cardiac performance, arteriole tone, neurosecretion, synaptic plasticity, and gene regulation. It has long been appreciated that DHPR activation of RyRs and subsequent calcium release from intracellular stores represents a key event in the control of these processes. In excitable cells, DHPRs trigger the release of intracellular calcium by promoting the opening of nearby RyRs (termed orthograde coupling). Interestingly, the signaling interaction between DHPRs and RyRs is often bi-directional such that the calcium-conducting activity of DHPR channels is also regulated by its interaction with the RyR (termed retrograde coupling). Recent data indicate that skeletal, cardiac, and neuronal cells utilize fundamentally distinct DHPR/RyR bi-directional coupling mechanisms (chemical and mechanical) in order to control the efficiency, fidelity, and activity of each of these two essential calcium channels. This review will focus on evaluating the nature and molecular determinants of these coupling mechanisms, as well as the extent to which excitable cell function is influenced by bi-directional DHPR/RyR calcium signaling.