Pleural sclerosis is indicated to obliterate the pleural space when one wants to prevent the recurrence of a spontaneous pneumothorax or the reaccumulation of a pleural effusion. Although many different agents ranging from antibiotics to antiseptics to antineoplastics to talc have been advocated, none is ideal. It is interesting that in the era when we are mapping the human genome, the agent most commonly used for pleurodesis is talc. Talc is very inhomogeneous, and the mechanisms by which it produces pleurodesis are unknown. In this review we will discuss the theory and mechanism of pleurodesis, the indications and contraindications for it, the advantages and disadvantages of the agents presently used for it, and our recommendations for the procedure.