Chronic pelvic pain (CPP) affects 12–15% of women worldwide. It is not a “functional somatic pain syndrome”, but a serious organic pain syndrome. It is the challenging clinical result of many previously neglected organ pathologies, when the alerting pain signals stemming from them have been disregarded or trivialized for years. Key “classic” contributors include endometriosis/adenomyosis, chronic bladder pain syndrome (BPS), vulvar vestibulitis (VVS)/provoked vestibulodynia (PV)/vulvodynia, irritable bowel syndrome (IBS), and pelvic inflammatory disease (PID). The current understanding of CPP complexities also recognizes new protagonists: gut microbiota, gut brain, pelvic floor muscles, and complex changes in pain processing and pain pathway organization. Tissue inflammation is the key pathophysiological feature, with mast cells (MCs) leading the process. Comorbidity, when inflammation involves different pelvic, abdominal, and distant organs, such as the brain, is the key clinical aspect. The underlying neuroinflammation contributes to anxiety and depression and worsens pain perception. Acute inflammation is physiological when it is the hallmark of a biological project finalized to restore tissue integrity and also when its duration and intensity are appropriate to complete the healing and resolving process. New-onset pain (nociceptive pain) is the tip of the iceberg of an underlying acute inflammatory process. The persistence of damaging factors, be it predisposing, precipitating, and/or maintaining, in each single organ involved shifts inflammation from acute to chronic. In parallel, pain becomes a disease when the underlying inflammation shifts from acute, short-living, and of limited intensity and resolving to chronic. Pain characteristics change, disrupting the pain system at the peripheral and central levels, until it becomes neuropathic and then nociplastic, a real disease per se. Immune system dysregulation is emerging as a common event in these conditions. Diagnosis is based on clinical history, to recognize key predisposing, precipitating, and maintaining factors contributing to pain in every organ involved. Pelvic and distant comorbidities, with a detailed physical examination and specific exams, complete the diagnostic process. Therapy should address different contributing pathophysiological processes with a multimodal approach, unified by a solid, embodied therapeutic vision.