The actions of proinflammatory cytokines in the CNS are only partially discovered. Some cytokines have been recently shown to affect neurotransmitters or are required to preserve the synaptic strength at excitatory synapses, or affect the expression of various neuropeptides and neurotrophic factors in several brain regions. Changes in the immune system may change the excitability of the CNS and alter the susceptibility of exogenous induced or genetically determined types of epilepsy. Here we investigate the role of two cytokines, IL-1β and TNF-α in WAG/Rij rats, a genetic model of absence epilepsy, the most pure form of generalized epilepsy characterized in the EEG by widespread bilaterally synchronous spike-wave discharges (SWDs) caused by thalamo-cortical oscillations. Our hypothesis is that cerebral blood flow alterations and cytokines/chemokines release can modulate the occurrence of SWDs. In this view, gene-array analysis for cell signaling pathways involved in SWDs in different cerebral areas, and qPCR data were correlated with EEG and MRS data. Furthermore, we analyzed the blood serum by ELISA method for TNF-α and IL-1β in control and epileptic animals; in addition, we injected i.p. both controls and WAG/Rij rats by TNF-α (2µg/kg) and IL-1β (2µg/kg). Our results indicate that a) cerebral blood volume and flow are altered in epileptic animals vs controls; b) slight differences have been noticed in TNF-α basal serum levels in early developmental stages (2 months) in WAG/Rij vs controls; c) TNF-α and IL-1β injections induced a large increase in the number of SDWs in WAG/Rij animals following a different time-pattern; d) MRS data indicate that WAG/Rij rats have higher levels of Glutamate vs controls, both in the thalamus and in the cerebral cortex; e) since cytokines have been reported to alter the neurotransmitters levels, we would like to further investigate the possible role of these mechanisms in this animal model. Summarizing, we hereby reported some evidences on the possible neuromodulator functions of inflammatory cytokines and absence epilepsy. Further study will allow to better elucidate these “liaisons dangereuses”.