In pharmacological studies conducted on animals over the last four decades, histamine was determined to be a strong modulator of learning and memory. Activation of histamine signaling enhances memory consolidation and retrieval. Even long after learning and forgetting, it can still restore the retrieval of forgotten memories. These findings based on animal studies led to human clinical trials with histamine H₃ receptor antagonists/inverse agonists, which revealed their positive effects on learning and memory. Therefore, histamine signaling is a promising therapeutic target for improving cognitive impairments in patients with various neuropsychiatric disorders, including Alzheimer’s disease. While the memory-modulatory effects of histamine receptor agonists and antagonists have been confirmed by several research groups, the underlying mechanisms remain to be elucidated. This review summarizes how the activation and inhibition of histamine signaling influence memory processes, introduces the cellular and circuit mechanisms, and discusses the relationship between the human histaminergic system and learning and memory.