Chromosome 16p11.2 deletions generally can result in a combination of developmental delay, behavioral, psychiatric and neurological problems, macrocephaly and difficult to treat childhood onset obesity, amongst other symptoms. There is a large clinical heterogeneity, also within families. Various different pathogenic 16p11.2 deletions have been distinguished. The most well-known are a so called typical 16p11.2 BP4-BP5 deletion, which often occurs de novo and a more distal 16p11.2 BP2-BP3 deletion, that importantly includes the SH2B1 gene. Involvement of the SH2B1 gene in the leptin-melanocortin pathway makes individuals with a distal 16p11.2 BP2-BP3 deletion particularly susceptible to the development of obesity and they are currently eligible for anti-obesity medication trials. In general, a complete multi-disciplinary evaluation of all individuals with pathogenic 16p11.2 deletion is recommended to provide personalized treatment and optimize care.