Nephrolithiasis treatment has become easier and less invasive with the development of extracorporeal shockwave lithotripsy (SWL) and endourologic techniques. However, medical therapy represents a well-established and complementary approach that can improve the efficacy of SWL and endourology. During recent decades, pharmacologic intervention has become more effective in stone disease: drugs can control the pain of renal colic, interfere at various levels in lithogenesis, and contribute to the expulsion of stones. It is well known that lithogenesis is a multifactorial process influenced by environmental-nutritional factors (low urinary volume, diet rich in animal protein, etc) and metabolic alterations; i.e., hypercalciuria, hyperuricosuria, and deficiency of stone-inhibiting factors (citrate, magnesium, glycosaminoglycans [GAGs]). Specific drugs such as citrate, allopurinol, and thiazide represent highly effective treatments for the promoting factors. Furthermore, recent findings suggest an interesting role for a phytotherapeutic agent, Phillantus niruri, and its inhibitory action on calcium oxalate crystallization related to the higher incorporation of GAGs into the calculi. Another step forward in medical management of stone disease is expulsive therapy. Many studies have proven the efficacy of medical expulsive therapy with nifedipine and alpha-blockers: their specific action on ureteral smooth muscle in association with anti-edema drugs accounts for their efficacy in expelling ureteral stones. In this paper, we provide an update on the medical treatment of stone disease, focusing our attention on what is known and what is new in renal colic and litholithic and expulsive medical therapy.