Lung cancer is the most common fatal malignant disease in the western world, accounting for 42,000 deaths each year in the UK alone. Small-cell lung cancer (SCLC), accounts for 25% of all lung cancers. It is a particularly aggressive form of the disease, characterised by widespread metastases and the development of resistance to chemotherapy. Even with combination chemotherapy and radiotherapy treatments, the 5-year survival is only about 5%. We review recent insights into the mechanisms underlying the development of metastases and resistance to chemotherapeutic agents in SCLC, focusing on the role of the extracellular matrix (ECM). We discuss the regulation of the interactions between cells and the ECM and the effects of these interactions on cellular phenotypes, together with some of the new approaches for combating drug resistance and metastases in this disease.