Among all animal models, the forced swimming test (FST) remains one of the mostly used tools for screening antidepressants with different mechanisms of action. This chapter reviews the main aspects of the FST in mice. Most of the sensitivity and variability factors that were assessed on the FST are summarized, as well as the most relevant data found in the literature of antidepressant effects on the FST in mice. From this data set, we have extrapolated some information about baseline levels of strain, and sensitivity against antidepressants. We have shown that many parameters have to be considered in this test to gain good reliability. Moreover, there was a fundamental inter-strain difference of response in the FST. The FST is a good screening tool with good reliability and predictive validity. Strain is one of the most important parameters to consider, for example Swiss and NMRI mice can be used to discriminate the mechanism of action of antidepressants; the CD-1 strain seems to be the most useful strain for screening purposes, but all results need to be arbitrated with spontaneous locomotor activity studies.