No low molecular weight (<20000) poly(ethylene glycol) (PEG) small molecule drug conjugates, prepared over a 20-year period, have led to a clinically approved product. In this area, published studies for these types of compounds have been scrutinized and their properties compared and contrasted to higher molecular weight conjugates where, during the past 5 years, a renaissance in the field of PEG (anticancer) drug conjugates has taken place. This new development has been attributed to the use of higher molecular weight PEGs (>20000), and especially employing PEG 40000 which is estimated to have a plasma circulating half life of approximately 8-9 h in the mouse. This recent resuscitation of small organic molecule delivery by high molecular weight PEG conjugates was founded on meaningful in vivo testing using established tumor models, and has led to a clinical candidate. Recent applications of high molecular weight PEG prodrug strategies to amino containing drugs are also detailed, and potential applications to proteins are proposed.