Global developmental delay (GDD) and intellectual disability (ID) occur in up to 3% of the general population and are even more commonly encountered in the setting of the pediatric neurology clinic. New advances in technology and in the understanding of genetic disorders have led to changes in the diagnostic approach to a child with unexplained GDD or ID. Chromosomal microarray has become a first-line test for evaluation of patients in this population and has both significantly increased diagnostic yield and introduced new challenges in the interpretation of copy number variants of uncertain significance. The G-banded karyotype is now frequently utilized as an adjunct to the microarray rather than as a first-line test in individuals with GDD or ID. Fragile X DNA testing continues to be recommended in the initial evaluation of the child with GDD or ID. The presence or absence of certain cardinal features (such as microcephaly or macrocephaly, seizures, autism, abnormal neurologic examination, and facial dysmorphism) can be utilized to direct single-gene molecular testing. The availability of next-generation and massively parallel sequencing technologies has enabled the use of genetic testing panels, in which dozens of genes associated with GDD or ID may be rapidly analyzed. Most recently, the clinical availability of whole-genome and whole-exome sequencing has opened new possibilities for the evaluation of individuals with GDD or ID who have previously eluded a genetic diagnosis. Consultation with a medical geneticist is recommended when progressing beyond first-tier analyses to most efficiently prioritize testing.