Homologous recombination repair (HRR) is a highly regulated DNA damage repair pathway responsible for high-precision repair of double strand breaks (DSBs). Cancer cells with homologous recombination deficiency (HRD) due to genomic and epigenomic alterations of HRR genes (such as BRCA1/2) display exacerbated genomic instability and hypersensitivity to platinum-based chemotherapy and inhibitors of the DNA repair enzyme poly-ADP ribose polymerase 1 (PARP1). This therapeutic vulnerability has been widely exploited for clinical management of several cancer types including ovarian, breast, prostate, and pancreatic cancer. However, a lack of reliable biomarkers allowing accurate HRD detection is a major factor limiting treatment access. As part of a multi-disciplinary effort to improve personalised cancer patient care, our team performs whole genome and transcriptome sequencing (WGTS)-based tumour profiling to inform clinical management of challenging cancers. Comprehensive assessment of HRD status is carried out by combining detection of genetic alterations in HRR genes, genomic instability, mutational signatures, as well as utilisation of genome-wide mutational scar-based HRD classifiers. This in-depth approach has allowed 1) expanded therapeutic options for eligible patients, especially for HRD tumours that carry mutations in noncanonical HRR genes or lack genomic alterations in DDR pathways; 2) better prediction of HRD status and therapy response, especially in tumours carrying HRD gene mutations of unknown significance, or mutations that predict therapy resistance; and 3) identification of resistance mechanisms in non-responder patients.