The signal transducer and activator of transcription (STAT) proteins have initially been described as cytoplasmic proteins that enter the nucleus only after cytokine treatment of cells. Contrary to this assumption, it was demonstrated that STATs are constantly shuttling between nucleus and cytoplasm irrespective of cytokine stimulation. This happens both via carrier-dependent as well as carrier-independent transportation. Moreover, it was also recognized that cytokine stimulation triggers nuclear retention of dimeric STATs, rather than affecting the rate of nuclear import. In summary, it is increasingly being appreciated that STAT nucleocytoplasmic cycling determines the quality of cytokine signaling and also constitutes an important area for microbial intervention.