Dual-specificity thyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a strong therapeutic target to ameliorate cognitive functions of Down Syndrome (DS). Genetic normalization of Dyrk1a is sufficient to normalize early cortical developmental phenotypes in DS mouse models. Gyrencephalic human neocortical development is more complex than that in lissencephalic mice; hence, cerebral organoids (COs) can be used to model early neurodevelopmental defects of DS. Single copy DYRK1A knockoutCOs (scDYRK1AKO-COs) can be generated frommanipulated DS derived (DS-) induced pluripotent stem cells (iPSCs) and genetic normalization of DYRK1A is expected to result in corrected neurodevelopmental phenotypes that can be reminiscent of normal COs. DYRK1A knock-in (DYRK1AKI) COs can be derived after genetic manipulations of normal iPSCs and would be valuable to evaluate impaired neocortical development as can be seen inDS-COs. DYRK1Amutations cause severe humanprimary microcephaly; hence, dose optimization studies of DYRK1A inhibitors will be critical for prenatal therapeutic applications in DS. Several doses of DYRK1A inhibitors can be tested in the neurodevelopment process of DS-COs and DS-scDYRK1AKO-COs would be used as optimummodels for evaluating phenotypic ameliorations. Overdose drug exposure inDS-COs can be explained by similar defects present in DS-baDYRK1AKO-COs and DYRK1AKO-COs. There are several limitations in the current CO technology, which can be reduced by the generation of vascularized brain-like organoids giving opportunities tomimic late-stage corticogenesis and complete hippocampal development. In the future, improved DS-DYRK1AKO-COs can be efficient in studies that aim to generate efficiently transplantable and implantable neurons for tissue regeneration alternatives in DS individuals.