Protein kinase-D (PKD) is increasingly recognized as a key regulatory signaling hub in cardiac glucose uptake and also a major player in the development of hypertrophy. Glucose is one of the predominant energy substrates for the heart to support contraction. However, a cardiac substrate switch toward glucose over-usage is associated with the development of cardiac hypertrophy. Hence, regulation of PKD activity must be strictly coordinated. This review provides mechanistic insights into the acute and chronic regulatory functions of PKD signaling in the healthy and hypertrophied heart. First an overview of the activation pathways of PKD1, the most abundant isoform in the heart, is provided. Then the various regulatory roles of the PKD isoforms in the heart in relation to cardiac glucose and fatty acid metabolism, contraction, morphology, function, and the development of cardiac hypertrophy are described. Finally, these findings are integrated and the possibility of targeting this kinase as a novel strategy to combat cardiac diseases is discussed.