Water solubility is a key parameter in drug formulation since it highly influences drug pharmacokinetics and pharmacodynamics. In the past decades, the challenge with poorly water soluble drugs has been growing continuously. As a matter of fact, poorly soluble compounds represent 40% of the top 200 oral drugs marketed in the US, 33% of drugs listed in the US Pharmacopeia, 75% of compounds under development and 90% of new chemical entities. The present article presents and discusses the pharmaceutical strategies available to overcome poor water solubility in light of final drug product examples. First, chemical modifications based on the adjustment of the pH and the design of prodrugs are presented and discussed. Physical modifications based on modified solid states of the drug, small drug particles, cosolvents, surfactants, lipids and cyclodextrins are discussed in a second part. Finally, the option of modifying the route of administration is briefly presented.