Adipose tissues are not homogeneous and show site-specific properties. An elusive and understudied adipose tissue depot, most likely due to its limited accessibility, is the intermuscular adipose tissue (IMAT) depot. Adipose tissue is a pliable organ with the ability to adapt to its physiological context, yet whether that adaptation is harmful or beneficial in the IMAT depot remains to be explored in humans. Potential reasons for IMAT accumulation in humans being deleterious or beneficial include 1) sex and related circulating hormone levels, 2) race and ethnicity, and 3) lifestyle factors (e.g., diet and physical activity level). IMAT quantity per se may not be the driving factor in the etiology of insulin resistance and type 2 diabetes, but rather the quality of the IMAT itself is the true puppeteer. Adipose tissue quality likely influences its secreted factors, which are also likely to influence metabolism of surrounding tissues. The advent of molecular assessments such as transcriptome sequencing (RNAseq), assay for transposase-accessible chromatin using sequencing (ATACseq), and DNA methylation at the single-cell and single-nucleus levels, as well as the potential for ultrasound-guided biopsies specifically for IMAT, will permit more sophisticated investigations of human IMAT and dramatically advance our understanding of this enigmatic adipose tissue.