Medullary sponge kidney (MSK) is a benign disorder associated with a lifetime risk of renal stones in 60% of patients. Patients frequently have episodic painless hematuria, but are often otherwise asymptomatic unless renal calculi or infections complicate the disease. Nephrolithiasis is a relative, but frequently enforced, contraindication to space or other high-performance flight. Two case reports of asymptomatic NASA flight crew with MSK and three cases of United States Air Force (USAF) military aviators diagnosed with MSK are reviewed. All cases resulted in waiver and return to flight status after treatment and a vigorous followup and prophylaxis protocol. MSK in aviation and spaceflight necessitates case-by-case evaluation and treatment to rule out other potential confounding factors that might also contribute to stone formation and in order to requalify the aviator for flight duties.