The 5-HT1A receptor is highly expressed both in 5-HT neurons as a presynaptic inhibitory autoreceptor, and in many brain regions innervated by 5-HT as a post-synaptic heteroreceptor. This review examines the signaling of 5-HT1A receptors to regulate 5-HT activity and behavior. Initial findings in heterologous cell systems, neuronal cell lines, neurons, and in vivo show that the 5-HT1A receptor is a Gi/o-coupled receptor that signals to the canonical pathway of inhibition of adenylyl cyclase (AC). However, new neuron-specific pathways and their roles in neuronal function have been uncovered. 5-HT1A receptor coupling via Gβγ subunits reduces neuronal activity by opening potassium channels and closing calcium channels. However, the receptor coupled primarily to Gi3 in 5-HT neurons and Gi2 in hippocampal neurons, which may underlie differential signaling and desensitization in these cells. While in 5-HT neurons, the 5-HT1A receptor appears to inhibit extracellular regulated protein kinase (ERK) ERK1/2 activity, it signals to activate it in developing and adult hippocampal neurons, and may play roles in synaptogenesis. Recent studies implicate 5-HT1A signaling through Gβγ and tyrosine kinase receptors to activate ACII, phospholipase C (PLC)/protein kinase C (PKC), calcium-calmodulin-dependent protein kinase II (CAMKII), and phosphatidyl inositol 3′-kinase (PI3K)/Akt signaling mediating synaptogenesis, cell survival, and behavioral actions of antidepressants. Thus, the 5-HT1A receptor appears to modify its signaling repertoire depending on the cell type (5-HT vs. post-synaptic neurons) and the developmental state of the neuron. Enhancement of cell specific signaling of the 5-HT1A receptor may provide an amplification of the antidepressant actions of 5-HT1A receptor activation. In addition, in response to prolonged 5-HT elevation upon chronic antidepressant treatment, the 5-HT1A autoreceptor appears to desensitize more extensively than the heteroreceptor. The mechanisms of 5-HT1A receptor desensitization are discussed, highlighting the potential of enhancing autoreceptor desensitization to accelerate antidepressant response.