Acute high-altitude (HA) illnesses (AHAIs), including acute mountain sickness (AMS), HA cerebral edema (HACE), and HA pulmonary edema (HAPE), represent significant health challenges for individuals rapidly ascending to high altitudes. Cytokines (interleukins (ILs)) and chemokines, which are involved in inflammatory and immunological responses, regulate the response of the body to hypoxic stress. Their dysregulation can contribute to the clinical symptoms of AMS, HACE, and HAPE by increasing vascular permeability, causing edema and damaging tissue. AHAIs elevate the levels of pro-inflammatory cytokines and chemokines, such as IL-17, tumor necrosis factor α (TNF-α), IL-1, IL-6, C-X-C motif chemokine ligand (CXCL) 10, CXCL8, C-C motif ligand 2 (CCL2 (CCL2), and CCL3, exacerbating symptoms. Thus, this review focuses on the cytokines and chemokines involved in AHAIs and the molecular mechanisms that extend beyond these cytokines and chemokines in clinical and preclinical contexts. Identifying these mediators and pathways helps researchers design drugs that reduce symptoms, slow disease progression, and enhance outcomes. Cytokines and chemokines have complex functions in these disorders and may serve as prospective therapeutic targets. Finally, we discuss treatment possibilities for AHAIs (drugs, exercise, and other inhibitors). This knowledge will help us to protect and improve the health of individuals at high altitudes.