The key takeaways from the first years of a sequencing program for rare childhood genetic diseases in Australia are published in this week's Journal of Medical Genetics, providing additional perspectives to launching such initiatives. The Murdoch Children's Research Institute's Undiagnosed Diseases Program-Victoria (UDP-Vic) recruits families with suspected rare genetic diseases who remain without a diagnosis after clinical genomic sequencing, and uses family-based exome and genome sequencing, RNA sequencing, and high-resolution chromosomal microarray with research-based analysis to search for answers. In this week's report, UDP-Vic members describe the lessons learned during its first three years — 2016 to 2018 — during which time 150 families were brought into the program. In those families, a diagnosis or strong candidate was achieved in 64 cases, most of which were made by familial exome sequencing. Among the lessons learned by UDP-Vic members is that flexible implementation of testing strategies, such as the selection of a subset of recruited families for resource-intensive testing, allowed the program to scale and respond to emerging technologies. Other conclusions involve the value of RNA sequencing for investigating variants of uncertain significance uncovered via genome or exome sequencing and the importance of data sharing to accelerate novel discoveries.