43 Small cell lung cancer (SCLC) remains one of the most aggressive forms of lung cancer, with patients often facing bleak survival rates despite initial treatment responses. Despite advances in other types of lung cancer, patients with SCLC continue to have limited treatment options. But a recent review of preclinical research suggests that there may be hope on the horizon with the potential for more personalised treatments. The findings were published in the journal Molecular Cancer. SCLC accounts for approximately 13 to 15% of all lung cancers. It is known for its rapid growth and early metastatic spread, which makes it especially challenging to treat. The current standard of care typically involves chemotherapy combined with radiation therapy, and in some cases, immunotherapy. While these treatments can lead to high response rates initially, almost all patients experience relapse, with limited success in second-line treatments. The five-year survival rate for SCLC remains dismal at below 7%. This poor prognosis has driven researchers to explore new avenues, with a particular focus on the molecular and genetic underpinnings of the disease. The current challenge lies in the fact that SCLC is often treated as a homogeneous disease, despite growing evidence that it can be subdivided into distinct molecular subtypes. One of the key discoveries highlighted in recent research is that SCLC can be classified into four molecular subtypes based on the expression of specific transcription factors: ASCL1, NEUROD1, POU2F3, and a newly emerging “inflamed” subtype. These subtypes display unique characteristics, including differences in how they respond to various treatments. Yet, despite this knowledge, clinical treatments have not yet been tailored to these subtypes, resulting in less effective treatment outcomes. Preclinical models have been crucial in uncovering new therapeutic targets for SCLC. These models include two-dimensional (2D) and three-dimensional (3D) cell cultures, as well as genetically engineered mouse models. These tools have allowed researchers to delve deeper into the biology of SCLC and identify potential vulnerabilities that could be exploited in treatment. For instance, certain subtypes of SCLC exhibit high expression of anti-apoptotic proteins like BCL-2, which can drive resistance to chemotherapy. Drugs targeting these proteins, such as venetoclax, have shown promise in preclinical models, particularly when used in combination with other therapies. Similarly, novel inhibitors targeting proteins like exportin-1 (XPO1) have been found to sensitize SCLC cells to chemotherapy, offering a potential new avenue for overcoming resistance. Immunotherapy has also emerged as a promising approach, particularly in combination with chemotherapy. Although SCLC has historically been less responsive to immune checkpoint inhibitors, recent preclinical studies suggest that creating an immune-permissive environment could enhance the efficacy of immunotherapy. This strategy could potentially lead to more durable responses, especially in patients with high tumour mutational burdens (TMB), who tend to respond better to immunotherapy. Despite these promising developments, researchers stress that more needs to be done. There is a strong call for incorporating molecular subtyping into clinical practice to guide treatment decisions. The hope is that by stratifying patients based on their tumour’s molecular profile, treatments can be tailored more effectively, leading to better outcomes.