Protein kinases are potential targets of drugs to treat many human diseases. Intensive efforts have been made to develop protein kinase inhibitors, but a major challenge is achieving specificity. Exploiting regulatory elements outside the ATP binding pocket, such as the substrate binding site, may provide an alternative that allows generation of competitive inhibitors with improved selectivity. In-depth understanding of substrate recognition by protein kinase is essential for design and refinement of competitive inhibitors. Here we described strategies for specifically targeting protein kinases and highlight our current progress in the development of substrate competitive inhibitors for glycogen synthase kinase-3 (GSK-3).