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Perineural invasion (PNI) is an important but under-reported route of metastasis of many cancers, in which neoplasm invades and spreads along the nerves. In recent years, PNI has been identified to contribute to the pathology of malignant tumors in the breast, stomach, head and neck, pancreas, prostate and large intestine. PNI of neoplasm may be attributable to poor prognosis of the patients, and sometimes appears to be the only cause of long-distance metastasis. Recent studies have furnished latest insights into the pathology and clinical features of PNI, characterized by continuous and interlinked multiple steps, starting from the formation of a perineural niche, comprising of neural cells, inflammatory cells, stromal cells, extracellular matrix, and blood vessels, in addition to the cancer cells. The critical step of PNI involves the establishment of connections between tumor and nerve through a number of signaling pathways consisting of soluble factors such as nerve growth factor, interleukins, and matrix metalloproteinases. Upon invasion into the nervous system, the cancer cells bring changes to neural cells and their microenvironment, leading to neoplastic spread along the nerves and alteration of normal nerve functions. In this review, we attempt to comprehensively cover the cellular and molecular mechanisms of perineural spread of tumors.