This commentary builds upon the recent study of Nair et al., 2022 entitled “A short-term chick embryo in vivo xenograft model to study retinoblastoma cancer stem cells” published in the Indian Journal of ophthalmology. The study describes an in vivo chick embryo-based xenograft model for the assessment of cancer stem cells (CSCs) in retinoblastoma. In this study, the authors have married the well-known and universally accepted chick embryo chorioallantoic membrane (CE-CAM) assay introduced by Auerbach et al., 1974[1] with their previous knowledge and experience on properties of CSCs in retinoblastoma[2] to develop an in vivo xenograft model.The authors have earlier demonstrated using flow cytometry-based study that the FSClo/SSClo/CD133lo subpopulations of Y79 retinoblastoma cells are the CSCs.[2] The authors also list the advantages of CE-CAM over the other transgenic and non-transgenic rodent models[34] in terms of short growth period, ease of manipulation and visualization, and also native immunodeficiency state, which makes it an ideal in vivo model for assessment. The authors have lucidly and elegantly carried out all the necessary experiments using gross morphological visualization, confocal/in vivo imaging techniques, and conventional histological techniques for demonstrating the usefulness of the CE-CAM assay in the assessment of metastasis in retinoblastoma. The use of imaging techniques for the assessment of tumor nodules and DiI-based spontaneous metastatic spread in the embryo need special mention. The assessment of the primary tumor in terms of the nodule and the metastasis by imaging correlates well with the histopathological findings validating the in vivo model.The authors themselves have specified the limitations in the current study and scope for future studies in terms of re-evaluation of the incubation period of the slow-growing tumor cells, use of less-invasive cell lines such as WERI-Rb1, and use of a more stable cell tracker such as Green fluorescent protein (GFP) in place of less stable DiI and enhanced imaging methods for the assessment of whole egg with the shell.Although the in vivo CE-CAM model has its own advantages compared to the current xenograft models of retinoblastoma, it may not be considered equivalent or less desirable to an orthotopic model,[5] which assesses the tumor in the native site and mimics the actual disease process in terms of primary tumor growth, metastatic activity, and response to therapeutics in countries with high economy.Given the low resources and minimal access to transgenic and immunodeficient rodent models in several developing countries including India, this method of integrating CE-CAM assay with the magnetic assisted cell sorting/flow cytometry-based sorting of CSCs seem to be highly beneficial in the clinical setting for the assessment of patient-derived xenografts for screening existing as well as novel therapeutics.