Pharmacophore approaches have become one of the major tools in drug discovery 
after the past century's development. Various ligand-based and structure-based 
methods have been developed for improved pharmacophore modeling and have been 
successfully and extensively applied in virtual screening, de novo design and 
lead optimization. Despite these successes, pharmacophore approaches have not 
reached their expected full capacity, particularly in facing the demand for 
reducing the current expensive overall cost associated with drug discovery and 
development. Here, the challenges of pharmacophore modeling and applications in 
drug discovery are discussed and recent advances and latest developments are 
described, which provide useful clues to the further development and application 
of pharmacophore approaches.