Recent studies highlight extensive crosstalk that exists between sensory neurons responsible for pain and the immune system. Cutaneous pain neurons detect harmful microbes, recruit immune cells, and produce anticipatory immunity in nearby tissues. These complementary systems generally protect hosts from infections. At the same time, neuroimmune pain is vulnerable to manipulation. Some pathogens evade immunity activated by nociceptors by producing opioid analogs and by interfering with sensory nerve function. Other organisms manipulate neuroimmune pain by increasing it. Hosts may gain protection from interference by adjusting pain sensitivity. Nociceptive sensitization follows expectations of signal detection theory and the smoke detector principle, allowing pain to be more easily triggered in response to microbial threats and damage. However, pain sensitization at the spinal level and cortical responses to pain are themselves the target of manipulation by parasites and other organisms. Here we review examples of parasites, bacteria, and other medically important organisms that interfere with pain signaling and describe their implications for public health, infectious disease, and the treatment of pain.