Histones, the structural unit of chromatin, must be assembled/dissembled to preserve or change chromatin organization in accordance to cellular needs. Initially, function of histone chaperones was thought to be only “histone carriers/vehicles”, but now with accumulating evidences they are known to be the key actors of histone metabolism. With this outburst of knowledge, histone chaperones are now placed at the center of gene regulation, having roles to play in DNA replication, repair and transcription. This review will focus on the current knowledge we have about the role of histone chaperones in regulating cellular processes and their relation to disease. In addition, we discuss the potential of histone chaperones as a therapeutic target.