The prefrontal cortex plays a principal role in higher cognition and particularly in the fast online manipulation of appropriate information to guide forthcoming behavior. Dysfunction of this process represents a main feature in the pathophysiology of schizophrenia. Both dopamine D1 and N-methyl-D-aspartate (NMDA) receptors in the prefrontal cortex play a critical role in synaptic plasticity, memory mechanisms, and cognition. Recent data have shown that D1 and NMDA receptors interact bidirectionally and may greatly influence the output of the prefrontal cortex. Hypofunction of these receptor systems in the prefrontal cortex is found in schizophrenia. This review attempts to summarize some of the latest findings on the cellular mechanisms that underlie D1-NMDA receptor interactions. These findings have provided potential therapeutic strategies that aim to functionally up-regulate D1 and/or NMDA receptor safely via selective activation of D1 receptors or coagonist activation of NMDA receptors through blockade of the glycine transporter-1.