Simple SummaryThe use of biomarkers can provide information about the outcome of cancer patients, the type of tumor, its malignant potential and the risk of recurrence, and may also be useful for guiding the selection of the optimal clinical treatment for the patient. There is sparse published information about the expression ofMALgene family members in cancer and their use as cancer biomarkers. On the other hand, large-scale studies have generated datasets that are freely available from public resources and that allow the expression of almost every human gene in multiple types of cancer to be analyzed. This review uses these two sources to investigate the expression of theMALgene family in cancer and to explore their potential biomedical applications as cancer biomarkers.AbstractThe MAL family of integral membrane proteins consists of MAL, MAL2, MALL, PLLP, CMTM8, MYADM, and MYADML2. The best characterized members are elements of the machinery that controls specialized pathways of membrane traffic and cell signaling. This review aims to help answer the following questions about theMAL-family genes: (i) is their expression regulated in cancer and, if so, how? (ii) What role do they play in cancer? (iii) Might they have biomedical applications? Analysis of large-scale gene expression datasets indicated altered levels ofMAL-family transcripts in specific cancer types. A comprehensive literature search provides evidence ofMAL-family gene dysregulation and protein function repurposing in cancer. ForMAL, and probably for other genes of the family, dysregulation is primarily a consequence of gene methylation, although copy number alterations also contribute to varying degrees. The scrutiny of the two sources of information, datasets and published studies, reveals potential prognostic applications ofMAL-family members as cancer biomarkers—for instance,MAL2in breast cancer,MAL2andMALLin pancreatic cancer, andMALandMYADMin lung cancer—and other biomedical uses. The availability of validated antibodies to some MAL-family proteins sanctions their use as cancer biomarkers in routine clinical practice.