The dual-specificity tyrosine-regulated kinase (DYRK) family is evolutionarily conserved from invertebrate to mammals. DYRKs regulate cell proliferation, apoptosis, survival, and differentiation by modifying the protein activation state, cellular localization, and turnover. In contrast to several studies in cellular models, the available evidence regarding the in vivo roles of DYRKs in mammalian development is limited. This review summarizes the in vivo studies on Dyrks which provide insight into their roles in mammalian tissue development and congenital diseases. In vivo evidence obtained using knockout and genetically modified animals helps to understand and develop novel clinical therapies and drug for human congenital diseases, such as Down syndrome and neuronal disorders (associated with DYRK1A) and skeletal ciliopathies (associated with DYRK2).