The use of next-generation sequencing technologies has enabled the rapid identification of non-synonymous somatic mutations in cancer cells. Neoantigens are mutated peptides derived from somatic mutations not present in normal tissues, that may result in the presentation of tumour-specific peptides capable of eliciting anti-tumour T-cell responses. Personalised neoantigen-based cancer vaccines and adoptive T-cell therapies have been shown to prime host immunity against tumour cells and are under clinical trial development. However, the optimisation and standardisation of neoantigen identification, as well as of its delivery as immunotherapy are needed to increase tumour-specific T-cells responses and, thus, the clinical efficacy of current cancer immunotherapies.In this recommendation article, launched by ESMO, we outline and discuss the available framework for neoantigen prediction and present a systematic review of the current scientific evidence.A number of computational pipelines for neoantigen prediction are available. Most of them provide peptide-MHC binding affinity predictions, but more recent approaches incorporate additional features like variant allele fraction, gene expression, and clonality of mutations. Neoantigens can be predicted in all cancer types with high and low tumour mutation burden, in part by exploiting tumour-specific aberrations derived from mutational frameshifts, splice variants, gene fusions, endogenous retroelements and other tumour-specific processes that could yield more potently immunogenic tumour neoantigens. Ongoing clinical trials will highlight those cancer types and combination of immune therapies that would derive most benefit from neoantigen-based immunotherapies.Improved identification, selection and prioritisation of tumour-specific neoantigens are needed to increase the scope of benefit from cancer vaccines and adoptive T-cell therapies. Novel pipelines are being developed to resolve the challenges posed by high-throughput sequencing and to predict immunogenic neoantigens.