The neurobiology of anxiety is complex, reflecting the cumulative physiological effects of multiple genes. These genes are interactive with each other and with the environment in which they are expressed. Variation in genes coding for proteins that control serotonin (5-HT) system development and plasticity, establish 5-HT neuron identity, and modulate 5-HT receptor-mediated signal transduction and cellular pathways have been implicated in the genetics of anxiety and related disorders. Here, we selected anxiety and avoidance as paradigmatic traits and behavior and cover both traditional studies with inbred murine strains and selected lines which have been modified by gene knockout technologies. The design of a mouse model partially or completely lacking a gene of interest during all stages of development (constitutive knockout) or in a spatio-temporal context (conditional knockout) is among the prime strategies directed at elucidating the role of genetic factors in fear and anxiety. In many cases, knockout mice have been able to confirm what has already been anticipated based on pharmacological studies. In other instances, knockout studies have changed views of the relevance of 5-HT homeostasis in brain development and plasticity as well as processes underlying emotional behavior. In this review, we discuss the pertinent literature regarding phenotypic changes in mice bearing inactivation mutations of 5-HT receptors, 5-HT transporter, monoamine oxidase A and other components of the serotonergic pathway. Finally, we attempt to identify future directions of genetic manipulation in animal models to advance our understanding of brain dysregulation characteristic of anxiety disorders.