Precision oncology based on specific genomic alterations has become a standard in the management of some tumours. Different studies (NCI-MATCH, TAPUR, DRUP, or MyPathway) have used a broader approach, testing multiple genes at the same time and assigning targeted therapies in basket trials. These studies showed some encouraging results supporting the potential use of next-generation sequencing in precision oncology. However, the application in head and neck cancer (except for salivary gland tumours) is still limited. The field is moving quickly into other approaches such as whole genome and transcriptome analysis. Transcriptome analyses have successfully helped in treatment decisions in some patients within prospective studies (WINTHER, POG). In head and neck cancer, gene expression signatures evaluating hypoxia or predicting anti-epidermal growth factor receptor (EGFR) therapy response, have been explored. As immunotherapy has become a standard in the treatment of squamous head and neck carcinoma, ribonucleic acid (RNA)-based immune signatures have been proposed to select those patients with higher probabilities of response. All these analyses are based on bulk transcriptomics. Nevertheless, understanding the role of each cell and its spatial configuration could be useful in precision oncology. In this sense, single-cell RNA sequencing could provide a better understanding of the different cell populations and their activities and potentially predict treatment response. Other immune-related biomarkers such as the T-cell receptor characteristics could provide an improved insight into the resistance to immunotherapy in patients with head and neck cancer. Non-coding genome analysis may contribute to a better understanding of the mechanisms of resistance or sensitivity to drugs and aid in discovering new therapeutic targets. However, most of the current precision medicine approaches rely on tumour tissue. This is a limitation for a broader applicability due to tumor heterogeneity and the need for tumour biopsies. Easy-to-access biomarkers such as circulating tumour deoxyribonucleic acid (ctDNA) could overcome both limitations as well as provide a more dynamic overview of the disease. Further understanding of molecular biology and tumour microenvironment including multi-institution collaborative initiatives and prospective studies is needed to translate these findings into our clinical practice.