Immune checkpoint inhibitors (ICIs) targeting CTLA-4 and the PD-1/PD-L1 axis have shown significant clinical activity in various cancers, transforming medical oncology. Unlike cytotoxic chemotherapy and targeted therapies, ICIs reinvigorate anti-tumour immune responses by disrupting co-inhibitory T-cell signaling. While resistance is common in patients treated with conventional therapies, durable responses suggestive of long-lasting immunologic memory are seen in many patients treated with ICIs. However, initial response appears binary, with most non-responders progressing at a rate consistent with the natural history of disease. Late relapses are emerging with longer follow-up, indicating the development of acquired resistance. Robust biomarkers to predict response and resistance remain elusive, and understanding the molecular and immunologic mechanisms underlying these responses and resistance is crucial. This review discusses emerging clinical and pre-clinical data on novel mechanisms of innate and acquired resistance to ICIs, highlighting the need for improved understanding to guide optimal combination/sequencing of ICIs in clinical practice.Immune checkpoint inhibitors (ICIs) targeting CTLA-4 and the PD-1/PD-L1 axis have shown significant clinical activity in various cancers, transforming medical oncology. Unlike cytotoxic chemotherapy and targeted therapies, ICIs reinvigorate anti-tumour immune responses by disrupting co-inhibitory T-cell signaling. While resistance is common in patients treated with conventional therapies, durable responses suggestive of long-lasting immunologic memory are seen in many patients treated with ICIs. However, initial response appears binary, with most non-responders progressing at a rate consistent with the natural history of disease. Late relapses are emerging with longer follow-up, indicating the development of acquired resistance. Robust biomarkers to predict response and resistance remain elusive, and understanding the molecular and immunologic mechanisms underlying these responses and resistance is crucial. This review discusses emerging clinical and pre-clinical data on novel mechanisms of innate and acquired resistance to ICIs, highlighting the need for improved understanding to guide optimal combination/sequencing of ICIs in clinical practice.