RASopathies are a group of clinically overlapping autosomal dominant disorders caused primarily by mutations in genes that reside along the canonical Ras-mitogen-activated protein kinase signaling cascade. Though individually rare, collectively, these disorders constitute one of the largest families of congenital disorders worldwide, particularly for infantile hypertrophic cardiomyopathy. Significantly, despite almost five decades of RASopathy research, therapeutic options remain limited and focused primarily on treating symptoms rather than disease etiology. Targeting the genes causal to these disorders, and the nodal pathways critical for their regulation, however, has been challenging. In this review, we highlight these challenges, particularly with respect to congenital heart defects and cardiac diseases and discuss limitations and future directions for approaches to new therapeutic strategies.