Sepsis is amongst the world's biggest public health problems with more than 20 million cases worldwide and a high morbidity rate of up to 50 %. Despite advances in modern medicine in the past few decades, incidence is expected to further increase due to an aging population and accompanying comorbidities such as cancer and diabetes. Due to the complexity of the disease, available treatment options are limited. Growing evidence links apoptotic cell death of lymphocytes and concomitant immune suppression to overall patient survival. In order to establish novel therapeutic approaches targeting this life threatening immune paralysis, researchers rely heavily on animal models to decipher the molecular mechanisms underlying this high impact disease. Here we describe variations of in vivo mouse models that can be used to study inflammation, cellular apoptosis, and survival in mice subjected to experimental polymicrobial sepsis and to a secondary infection during the immune suppressive secondary stage.