Throughout the past decade, much effort has been spent on deciphering the signaling pathways positively mediating cardiac hypertrophy. Recently, several endogenous molecules in the heart have been shown to negatively regulate cardiac hypertrophy. One group of these molecules is constitutively active at baseline, while molecules belonging to the second group serve as negative feedback regulators, which are activated in response to pathologic insults. Studies upon the negative regulators of cardiac hypertrophy may allow us to develop novel strategies to treat heart failure by mimicking the naturally preferred mechanisms to maintain homeostasis. In addition, the search for molecular targets of these negative regulators may allow us to identify novel positive mediators of hypertrophy. The aim of this article is to provide a brief overview of these newly identified negative regulators of cardiac hypertrophy.