The simultaneous and/or concurrent use of licit and illicit substances (polysubstance use, PSU) is most common today. Structural magnetic resonance imaging (MRI) has been applied extensively to study individuals ostensibly using a single substance. These studies have produced a picture of regional gray matter and white matter alterations with each substance or class of substances. Very few studies measured regional brain morphometry in today's polysubstance users. This limited data suggest morphometric alterations with PSU that are not simply additive but often different from those of monosubstance users. Specifically, subcortical volume enlargements are observed that may be tied to mechanisms that also oppose volume reductions in cortical brain regions, thereby underestimating actual cortical atrophy. The complex actions of polysubstance use on brain structure and function need greater scrutiny with strong methodological approaches to inform more efficient treatment of polysubstance users.