Schizophrenia (SZ) is a multifaceted mental disorder characterized by disturbances in thinking, perception, emotions, and behavior causing substantial disability and economic challenges for individuals with SZ, their family, caregivers, and society in general. The variety of SZ symptoms, which are broadly categorized into positive, negative, and cognitive dimensions, are strongly correlated with structural changes and functional alterations of brain regions involved in core sensory, cognitive, and regulatory systems. Here, it is presented and discussed multiple lines of preclinical and clinical evidence that converge in indicating that hyperactivity and hypoactivity of brain regions involved in SZ symptoms emerge from deficits in neuronal communication and synaptic dysfunction. It is also discussed the extent to which alterations in excitatory (E) and inhibitory (I) systems correlate with brain hyperactivity, or hypoactivity, and how those alterations correlate with SZ symptoms. Major synaptic proteins found associated with SZ risk in large genomics studies are discussed in the context of E/I imbalance and SZ symptoms. Lastly, novel FDA-approved medications that address synaptic imbalance are briefly discussed. Understanding the regional synaptic imbalances is crucial for developing targeted interventions aimed at restoring synaptic function and ameliorating the cognitive and behavioral symptoms that are major drivers of disability in SZ.