Undoubtedly, adjusting our thermoregulatory behavior represents the most effective mechanism to maintain thermal homeostasis and ensure survival in the diverse thermal environments that we face on this planet. Remarkably, our thermal behavior is entirely dependent on the ability to detect variations in our internal (i.e. body) and external environment, via sensing changes in skin temperature and wetness. In the past 30 years, we have seen a significant expansion of our understanding of the molecular, neuroanatomical and neurophysiological mechanisms that allow humans to sense temperature and humidity. The discovery of temperature-activated ion channels which gate the generation of action potentials in thermosensitive neurons, along with the characterization of the spino-thalamo-cortical thermosensory pathway, and the development of neural models for the perception of skin wetness, are only some of the recent advances which have provided incredible insights on how biophysical changes in skin temperature and wetness are transduced into those neural signals which constitute the physiological substrate of skin thermal and wetness sensations. Understanding how afferent thermal inputs are integrated and how these contribute to behavioral and autonomic thermoregulatory responses under normal brain function is critical to determine how these mechanisms are disrupted in those neurological conditions which see the concurrent presence of afferent thermosensory abnormalities and efferent thermoregulatory dysfunctions. Furthermore, advancing the knowledge on skin thermal and wetness sensations is crucial to support the development of neuro-prosthetics. In light of the above, this review will focus on the peripheral and central neurophysiological mechanisms underpinning skin thermal and wetness sensations in humans.