Complex chromosomal rearrangements (CCRs) are rearrangements involving more than two chromosomes or more than two breakpoints. Whole genome sequencing (WGS) allows for outstanding high resolution characterization on the nucleotide level in unique sequences of such rearrangements, but problems remain for mapping breakpoints in repetitive regions of the genome, which are known to be prone to rearrangements. Hence, multiple complementary WGS experiments are sometimes needed to solve the structures of CCRs. We have studied three individuals with CCRs: Case 1 and Case 2 presented with de novo karyotypically balanced, complex interchromosomal rearrangements (46,XX,t(2;8;15)(q35;q24.1;q22) and 46,XY,t(1;10;5)(q32;p12;q31)), and Case 3 presented with a de novo, extremely complex intrachromosomal rearrangement on chromosome 1. Molecular cytogenetic investigation revealed cryptic deletions in the breakpoints of chromosome 2 and 8 in Case 1, and on chromosome 10 in Case 2, explaining their clinical symptoms. In Case 3, 26 breakpoints were identified using WGS, disrupting five known disease genes. All rearrangements were subsequently analyzed using optical maps, linked-read WGS, and short-read WGS. In conclusion, we present a case series of three unique de novo CCRs where we by combining the results from the different technologies fully solved the structure of each rearrangement. The power in combining short-read WGS with long-molecule sequencing or optical mapping in these unique de novo CCRs in a clinical setting is demonstrated. Author summary Unexpected complexities are common findings in the breakpoints of karyotypically balanced complex chromosomal rearrangements (CCRs). Such findings are of clinical importance, as they may be the cause of mendelian phenotypes in the rearrangement carrier. Whole genome sequencing (WGS) allows for high resolution characterization of CCRs, but problems remain for mapping breakpoints located in repetitive regions of the genome, which are known to be prone to rearrangements. In our study, we use multiple complementary WGS experiments to solve the structures of three CCRs originally identified by karyotyping. In all cases, the genomic structure of the derivative chromosomes was resolved and a molecular genetic explanation of the clinical symptoms of the patients was obtained. Furthermore, we compare the performance, sensitivity and resolution of four different WGS techniques for solving these CCRs in a clinical diagnostic laboratory set.