Bipolar disorder (BPD) is characterized by vulnerability to episodic depression and mania and spontaneous cycling. Because of marked advances in candidate-gene and genome-wide association studies, the list of risk genes for BPD is growing rapidly, creating an unprecedented opportunity to understand the pathophysiology of BPD and to develop novel therapeutics for its treatment. However, genetic findings are associated with major unresolved issues, including whether and how risk variance leads to behavioral abnormalities. Although animal studies are key to resolving these issues, consensus is needed regarding how to define and monitor phenotypes related to mania, depression and mood swing vulnerability in genetically manipulated rodents. In this study we discuss multiple facets of this challenging area, including theoretical considerations, available tests, limitations associated with rodent behavioral modeling and promising molecular-behavioral findings. These include CLOCK, glycogen synthase kinase 3beta (GSK-3beta), glutamate receptor 6 (GluR6), extracellular signal-regulated kinase-1 (ERK1), p11 (or S100A10), vesicular monoamine transporter 2 (VMAT2 or SLC18A2), glucocorticoid receptors (GRs), Bcl-2-associated athanogene-1 (BAG1) and mitochondrial DNA polymerase-gamma (POLG). Some mutant rodent strains show behavioral clusters or activity patterns that cross-species phenocopy objective/observable facets of mood syndromes, and changes in these clustered behaviors can be used as outcome measures in genetic-behavioral research in BPD.