Hyporesponsiveness (immune tolerance) follows vaccination with meningococcal polysaccharide and many pneumococcal polysaccharide serotypes. Hyporesponsiveness after Haemophilus influenzae type b polysaccharide vaccination has not been directly observed, but may follow exposure during disease in some individuals. Use of currently licensed conjugate vaccines has not been associated with hyporesponsiveness to date, with the possible exception of pneumococcal serotype 3. Introduction of polysaccharide vaccines anywhere into a conjugate vaccination schedule may result in reduced immune responses on subsequent exposure. This review of vaccine-induced hyporesponsiveness and its potential clinical implications considers recent evidence suggesting that hyporesponsiveness may occur for specific components of combined conjugate vaccines, such as pneumococcal serotype 3. These data have implications for the development of new multivalent vaccines.