Substance P (SP) is upregulated in HIV infection in adult men and women, as determined by increased plasma levels. There is a reciprocal and bidirectional relationship between substance P and HIV in HIV‐infected monocyte‐derived macrophages and cell lines (e.g., THP‐1). Substance P up‐regulates HIV and HIV up‐regulates SP protein expression. Neurokinin‐1 receptor (NK1R) antagonists inhibit HIV infectivity through downregulation of the chemokine receptor, CCR5, and downregulation of HIV LTR. Neurokinin‐1 receptor is expressed in full‐length and truncated forms. The full‐length NK1R is capable of signaling, whereas the truncated NK1R primes the chemokine receptor CCR5. Both full‐length and truncated NK1R are expressed in several brain regions in human autopsy brains. SP–NK1R interactions have regulatory roles in inflammation and infection. The differential expression of truncated and full‐length NK1R has important biological consequences. These include receptor–receptor interaction (e.g., NK1R–CCR5); changes in expression during cell differentiation (e.g., THP‐1 cells); and differences in regional tissue distribution (e.g., differences in different brain regions). NK1R‐SP receptor pathways are important cell regulatory pathways.