The rostral intralaminar thalamic nuclei (ILn) are organized to activate pathways originating in medial prefrontal cortex (mPF) that mediate memory-guided responding during alert, wakeful states. Previous studies have shown that rostral ILn or mPF lesions produce deficits in delayed matching to position (DMTP). Here, we manipulated rostral ILn activity in rats by microinjecting drugs or applying electrical current and examined effects on DMTP. Inhibiting activity with the GABA(A) agonist muscimol impaired DMTP. Decreasing GABA(A) tone with FG-7142 (N-methyl-beta-carboline-3-carboxamide) improved DMTP at low but not high doses. Orexin A, which depolarizes thalamocortical neurons locally within the ILn, improved DMTP, whereas the cholinergic agonist carbachol impaired performance at the highest dose tested. These drug effects were unaffected by partial mPF lesions in a subset of animals. Microinjection results are consistent with an inverted-U relationship between thalamic activity and DMTP. This relationship was confirmed by event-related electrical stimulation, which produced improvement at low stimulation currents and impairment at higher currents. Electrical stimulation affected DMTP when applied at the start of the memory delay or choice response, but not earlier when trials began or the sample lever was presented. Our results are consistent with evidence that the rostral ILn play a role in retrieval, carrying response-related information across brief memory delays and facilitating memory-guided responding. They also provide evidence that treatments stimulating rostral ILn activity may be an effective means to enhance working memory and related cognitive processes and thus to treat disorders that affect these functions.