Low-level laser therapy (LLLT) has been used in many clinical contexts. Although its precise mechanism is unclear, its current use is based predominantly on its non-invasive nature and popular patient acceptance. This review attempts to provide a framework for the clinical disease-disorder states focusing on the etiopathology namely; pain, inflammation and immune response termed the PII axis. Following a brief introduction, the literature on the ability of LLLT to modulate the PII axis in specific disease states is reviewed. The triad of critical parameters for LLLT namely, the dose, the biological context and the mechanism are highlighted. This work suggests that LLLT could be a potent primary interventional modality when used to specifically target the PII axis in clinical disease management.