Small molecules, a growing class of targeted therapies, have flourished over the last decade. With increased knowledge on molecular cell signaling, targeted therapy has been refined to targeting molecular targets upstream from the nucleus that are key players in the communication system that regulates cancer cell growth. This article reviews the mechanisms of small molecules with a particular emphasis on tyrosine kinase inhibitors, as well as the literature that supports the current clinical use in the treatment of a variety of solid and hematological malignancies.