This review focuses on the lower urinary tract, specifically addressing key immunological and microbiological aspects of infectious and inflammatory conditions such as urethritis, interstitial cystitis/bladder pain syndrome (IC/BPS), urinary tract infections (UTIs), and urosepsis. The urinary tract, including the urethra and bladder, is subject to frequent exposure to pathogens, which are managed through mechanical defenses and physiological barriers. The urinary tract expresses a variety of antimicrobial peptides and proteins, and the presence of a mucosal membrane composed of urothelium and glycosaminoglycan (GAG) layers provides additional protection. The immune landscape in the urethra and bladder involves various immune cells and receptors, including TLRs, mast cells, and macrophages, which play crucial roles in mounting an immune response. The urinary tract microbiome, or "urobiome," is also discussed, highlighting its role in health and disease. Changes in the urobiome have been observed in various conditions, and metabolites produced by the urobiome may influence immune activation in chronic kidney disease. Urethritis, often caused by sexually transmitted infections (STIs) or UTIs, is characterized by symptoms such as urethral discharge, dysuria, and frequency. Empirical treatment strategies are commonly used, but the increasing prevalence of M. genitalium poses challenges due to the risk of macrolide resistance. Interstitial cystitis (IC) and related conditions, such as bladder pain syndrome (BPS), are inflammatory disorders affecting the bladder. IC/BPS can be divided into Hunner type (HIC) and BPS subtypes, with HIC characterized by characteristic lesions and chronic inflammation. Management strategies include conservative approaches, surgical resection, and hydrodistension therapy, with novel therapies like liposome-based treatments and cannabinoids showing potential. UTIs, which can occur in any part of the urinary tract, are classified as uncomplicated or complicated based on risk factors. UPEC is the most common pathogen, and the incidence of UTIs increases with age. Catheterization is a significant risk factor for UTIs, and the pathogens often form biofilms. Diagnosis and treatment are guided by clinical factors and urine culture results, with antibiotic stewardship being crucial to manage resistance. Urosepsis, a life-threatening condition, can result from a dysregulated host response to infection originating from the urinary tract. Risk factors include anatomical abnormalities, urodynamics, and immune-compromising co-morbidities. The review emphasizes the importance of understanding the immunological and microbiological aspects of these conditions to develop new therapeutic options and improve patient outcomes.This review focuses on the lower urinary tract, specifically addressing key immunological and microbiological aspects of infectious and inflammatory conditions such as urethritis, interstitial cystitis/bladder pain syndrome (IC/BPS), urinary tract infections (UTIs), and urosepsis. The urinary tract, including the urethra and bladder, is subject to frequent exposure to pathogens, which are managed through mechanical defenses and physiological barriers. The urinary tract expresses a variety of antimicrobial peptides and proteins, and the presence of a mucosal membrane composed of urothelium and glycosaminoglycan (GAG) layers provides additional protection. The immune landscape in the urethra and bladder involves various immune cells and receptors, including TLRs, mast cells, and macrophages, which play crucial roles in mounting an immune response. The urinary tract microbiome, or "urobiome," is also discussed, highlighting its role in health and disease. Changes in the urobiome have been observed in various conditions, and metabolites produced by the urobiome may influence immune activation in chronic kidney disease. Urethritis, often caused by sexually transmitted infections (STIs) or UTIs, is characterized by symptoms such as urethral discharge, dysuria, and frequency. Empirical treatment strategies are commonly used, but the increasing prevalence of M. genitalium poses challenges due to the risk of macrolide resistance. Interstitial cystitis (IC) and related conditions, such as bladder pain syndrome (BPS), are inflammatory disorders affecting the bladder. IC/BPS can be divided into Hunner type (HIC) and BPS subtypes, with HIC characterized by characteristic lesions and chronic inflammation. Management strategies include conservative approaches, surgical resection, and hydrodistension therapy, with novel therapies like liposome-based treatments and cannabinoids showing potential. UTIs, which can occur in any part of the urinary tract, are classified as uncomplicated or complicated based on risk factors. UPEC is the most common pathogen, and the incidence of UTIs increases with age. Catheterization is a significant risk factor for UTIs, and the pathogens often form biofilms. Diagnosis and treatment are guided by clinical factors and urine culture results, with antibiotic stewardship being crucial to manage resistance. Urosepsis, a life-threatening condition, can result from a dysregulated host response to infection originating from the urinary tract. Risk factors include anatomical abnormalities, urodynamics, and immune-compromising co-morbidities. The review emphasizes the importance of understanding the immunological and microbiological aspects of these conditions to develop new therapeutic options and improve patient outcomes.