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Reprogramming of lipid metabolism is emerging as a hallmark of cancer, yet involvement of specific fatty acids (FA) species and related enzymes in tumorigenesis remains unclear. While previous studies have focused on involvement of long‐chain fatty acids (LCFAs) including palmitate in cancer, little attention has been paid to the role of very long‐chain fatty acids (VLCFAs). Here, we show that depletion of acetyl‐CoA carboxylase (ACC1), a critical enzyme involved in the biosynthesis of fatty acids, inhibits both de novo synthesis and elongation of VLCFAs in human cancer cells. ACC1 depletion markedly reduces cellular VLCFA but only marginally influences LCFA levels, including palmitate that can be nutritionally available. Therefore, tumor growth is specifically susceptible to regulation of VLCFAs. We further demonstrate that VLCFA deficiency results in a significant decrease in ceramides as well as downstream glucosylceramides and sphingomyelins, which impairs mitochondrial morphology and renders cancer cells sensitive to oxidative stress and cell death. Taken together, our study highlights that VLCFAs are selectively required for cancer cell survival and reveals a potential strategy to suppress tumor growth. Synopsis: While fatty acids (FA) are established to fuel cellular growth, involvement of specific lipid species in cancerogenesis remains poorly understood. Here, combined genetics and global lipid metabolomics uncover requirement of very long‐chain fatty acids (VLCFAs) and acetyl‐CoA carboxylase (ACC1) for tumor growth, suggesting novel therapeutic avenues. ACC1 depletion reduces VLCFA but not long‐chain fatty acid levels in human cancer cells.VLCFA elongation enhances tumor growth in xenograft models.VLCFA deficiency results in a significant decrease in ceramides as well as downstream glucosylceramides and sphingomyelins.VLCFA deficiency impairs mitochondrial morphology and renders cancer cells sensitive to oxidative stress. [ABSTRACT FROM AUTHOR]