<p>Spheroids, organoids, and further three-dimensional cellular models represent an intermediate stage of supra-cellular complexity between monolayered cell cultures and animal models. In the present review, we identified conditions in which spheroids and organoids could replace animal models in biomedical research, using long noncoding RNA (lncRNA) research in cancer as a study object. In tumor spheroids and patient-derived organoids, chemosensitivity can be enhanced through therapeutic overexpression or silencing of specific lncRNAs (depending on the lncRNA and context), which then decreases spheroid/organoid size or formation efficiency. These outcomes consistently mimic observations in xenograft mouse models, in which the same lncRNA intervention decreases tumor volume. Therefore, as a proxy of tumor growth assessment, animal models could be largely replaced with spheroids or organoids, taking advantage of their inexpensiveness and patient-specific features, respectively. The use of animal models could be restricted to bystander or pleiotropic effects, such as the assessment of parameters including metastasis and survival rates.</p>