X-ray fluorescence CT (XFCT), a novel modality proposed for high-sensitivity high-resolution molecular imaging of probes labelled with a high atomic-number element, has been performed with high-energy K-shell X-rays. XFCT performed with low-energy L-shell X-rays could, in principle, result in an increase of XFCT imaging sensitivity; however, the significant L-shell X-ray attenuation limits its use for imaging of small objects. This commentary discusses the advantages and drawbacks of L-shell XFCT imaging.