Synchronous, rhythmic changes in the membrane polarization of neurons form oscillations in local field potentials. It is hypothesized that high-frequency brain oscillations reflect local cortical information processing, and low-frequency brain oscillations project information flow across larger cortical networks. This provides complex forms of information transmission due to interactions between oscillations at different frequency bands, which can be rendered with cross-frequency coupling (CFC) metrics. Phase-amplitude coupling (PAC) is one of the most common representations of the CFC. PAC reflects the coupling of the phase of oscillations in a specific frequency band to the amplitude of oscillations in another frequency band. In a normal brain, PAC accompanies multi-item working memory in the hippocampus, and changes in PAC have been associated with diseases such as schizophrenia, obsessive-compulsive disorder (OCD), Alzheimer disease (AD), epilepsy, and Parkinson's disease (PD). The purpose of this article is to explore CFC across the central nervous system and demonstrate its correlation to neurological disorders. Results from previously published studies are reviewed to explore the significant role of CFC in large neuronal network communication and its abnormal behavior in neurological disease. Specifically, the association of effective treatment in PD such as dopaminergic medication and deep brain stimulation with PAC changes is described. Lastly, CFC analysis of the electrocorticographic (ECoG) signals recorded from the motor cortex of a Parkinson's disease patient and the parahippocampal gyrus of an epilepsy patient are demonstrated. This information taken together illuminates possible roles of CFC in the nervous system and its potential as a therapeutic target in disease states. This will require new neural interface technologies such as phase-dependent stimulation triggered by PAC changes, for the accurate recording, monitoring, and modulation of the CFC signal.