Puberty is a critical period of development during which sexual maturity is attained. It is also a critical period for brain reorganization and it is vulnerable to exposure to certain environmental factors. Exposure to stress during this period can cause enduring neural and behavioral alterations. More specifically, exposure to an immune challenge during this period can alter reproductive as well as a number of non-reproductive behaviors and can permanently alter the brain’s response to gonadal hormones. The present review examines the enduring effect of exposure to LPS and poly(I:C) during the pubertal period. Age and sex differences in acute response to LPS are discussed as possible mechanisms of vulnerability to adverse effects. Moreover, this review suggests new research directions to improve our understanding of the vulnerability of the pubertal period to immunological stressors.