This dataset accompanies the manuscript “Calpain-1 and calpain-2 promote breast cancer metastasis” and contains raw image data underlying the in vivo tumor biology and metastasis figures (Fig. 3 and Fig. 5) and the related supplementary analyses. Using MDA-MB-231 triple-negative breast cancer cells, we generated CRISPR/Cas9 knockouts of CAPN1, CAPN2, and CAPNS1 (the two catalytic and the common regulatory subunit required for calpain-1/2 heterodimers). The data contain images of lungs and of microscopic randomly selected regions of interest thereof harvested from the calpain-deficient tumor bearing Rag2-/-IL2Rgc-/- mice, fluorescently imaged in a GFP channel (Ex/Em: 488/510nm); each hyperintense nodule is a GFP-positive metastatic lesion. Abbreviations: CAPN1, C1 - calpain-1 catalytic subunit. CAPN2, C2 - calpain-2 catalytic subunit. CAPNS1, S1 - calpain small regulatory subunit 1. KO - CRISPR/Cas9 gene knockout. R - gene rescue, addback.