The consequences of T-cell receptor engagement (signal 1) are profoundly affected by the presence or absence of co-stimulation (signal 2). T-cell receptor (TCR) stimulation in the absence of CD28-mediated co-stimulation not only results in little interleukin (IL)-2 production, but induces a long lasting hyporesponsive state known as T-cell clonal anergy. The addition of CD28 ligation to signal 1, on the other hand, results in the production of copious amounts of IL-2. Our laboratory has utilized CD4+ Th1 clones in an effort to understand the molecular events resulting in enhanced IL-2 production by co-stimulation and the inhibition of IL-2 production in anergy. Our current studies have focused on defining the post-transcriptional effects of CD28-enhanced IL-2 production. The data suggest that a major component of CD28's ability to regulate IL-2 production occurs at the level of message stability and involves the 3′-untranslated region of the message. In terms of anergy, our recent studies support the notion that it is not the result of TCR engagement in the absence of co-stimulation, but rather signal 1 in the absence of IL-2 receptor signaling and proliferation. Furthermore, T-cell anergy appears to be an active negative state in which IL-2 production is inhibited both at the level of signal transduction and by cis-dominant repression at the level of the IL-2 promoter.