The activity-regulated transcription factor cAMP response element-binding protein (CREB) is an essential component of the molecular switch that controls the conversion of short-term into long-term forms of plasticity, including those underlying long-term memory. Previous research in acute brain slices of transgenic animals expressing constitutively active CREB variants has revealed that enhancing CREB activity increases the intrinsic excitability of neurons and facilitates the late phase of long-term potentiation (LTP) in the Schaffer collateral pathway. Here, we report similar changes in plasticity at the Schaffer collateral pathway in alert behaving mice. Forebrain expression of a strong constitutively active CREB variant, VP16-CREB, enhanced in vivo LTP evoked in the Schaffer collateral pathway and caused significant changes in the input/output curve and paired-pulse facilitation in CA3-CA1 synapses, which could be explained by the increased excitability of hippocampal pyramidal neurons. In addition, classical eyeblink conditioning in transgenic mice and control littermates showed larger conditioned responses in mutant mice that were associated to a transient increase in the acquisition rate and in the concomitant learning-dependent change in synaptic strength. The sustained chronic activation of CREB activity, however, impaired the performance in this task. Our experiments demonstrate that the sustained enhancement of CREB function alters the physiology and plasticity of hippocampal circuits in behaving animals and that these changes have important consequences in associative learning.