Although for decades autosomal dominant polycystic kidney disease (ADPKD) was considered a disease of adults, our recent longitudinal studies on children from ADPKD families have shown that the disease is evident by ultrasound imaging in approximately 75% of children who are carriers of the ADPKD1 gene, the most common form of ADPKD. Here we report that, in contrast to adults, the disease appears to be unilateral initially in approximately 17% of children. Asymmetric enlargement of the kidneys is also frequently observed. This renal asymmetry can be extreme and lead to diagnostic confusion. We present 2 unusual cases of asymmetric renal involvement that we have observed during the last 10 years. The first is a 14-year-old boy who was scheduled for a nephrectomy to relieve pain and whose family requested a second opinion. The second is a 10-year-old girl who was diagnosed with ADPKD in utero by prenatal ultrasound. After birth, 1 kidney progressively developed cysts and enlarged, whereas the other had only a few tiny cysts and remained normal in size. A review of the literature shows that presentations like these often lead to a nephrectomy or surgical biopsy. A carefully obtained family history and examination of both parents with ultrasound can help to avoid unnecessary invasive procedures. If pain is a prominent symptom, it can be treated by cyst aspiration if there are only a few cysts or a single dominant cyst. The molecular mechanism for extremely asymmetric renal disease remains to be elucidated.