A critical requirement for the conversion of the labile short-term memory (STM) into the consolidated long-term memory (LTM) is new gene expression (new mRNAs and protein synthesis). The first clues to the molecular mechanisms of the switch from short-term to LTM emerged from studies on protein synthesis in different species. Initially, it was shown that LTM can be distinguished from STM by its susceptibility to protein synthesis inhibitors. Later, it was found that long-lasting synaptic changes, which are believed to be a key cellular mechanism by which information is stored, are also dependent on new protein synthesis. Although the role of protein synthesis in memory was reported more than 40 years ago, recent molecular, genetic, and biochemical studies have provided fresh insights into the molecular mechanisms underlying these processes. In this chapter, we provide an overview of the role of translational control by the eIF2alpha signaling pathway in long-term synaptic plasticity and memory consolidation.