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Cell motility within adult animals underlies a wide range of critical processes, including trafficking in disease and tissue repair. Cells in the periphery of a tumor, for example, crawl through surrounding tissue and ECM to divide or metastasize into narrow vessels (Weinberg, 2006). Multipotent stem cells in the bone marrow likewise transmigrate into blood capillaries or other tissues far from their niche and have potential roles in tissue regeneration (Pittenger and Martin, 2004) as well as cancer (Houghton et al., 2004; Nakamizo et al., 2005). Successful migration requires cells to survive large distortions (Fig. 1 A), but the largest single organelle in every cell is typically the nucleus—which tends to be stiff (Dahl et al., 2005; Lammerding et al., 2006; Pajerowski et al., 2007). In light of the considerable stress generated by the cytoskeleton in crawling through tissue matrix (Mierke et al., 2011), we hypothesized rate-limiting roles for nuclear mechanics in both 3D migration and post-migration survival. Aand B-type lamins are intermediate filaments that assemble with distinct membrane-binding partners into juxtaposed networks within the nuclei of nearly all adult animal cells (Moir et al., 2000; Holaska et al., 2002; Shimi et al., 2008). Yeast cells do not express lamins (Dittmer and Misteli, 2011) and do not migrate, but have rigid cell walls that physically protect their genomes. Why animal cells have two independent nucleoskeletal networks is unclear, but each lamin type might distinctly modulate gene expression (Dechat et al., 2008) and each lamin type might also stiffen and stabilize the nucleus with a distinctiveness similar to that of the many different keratin intermediate filaments in skin, nails, hair, and beaks. For migration, the polymorphonuclear leukocyte (PMN) is perhaps instructive in that it down-regulates lamins in differentiation to a cell with a multi-segmented nucleus (Olins et al., 2001) of a flexibility suitable for crawling through very small pores in endothelium and dense tissues (Chamberlain and Lichtman, 1978). However, PMNs also die within days (Pillay et al., 2010), perhaps because the chromatin is unprotected. Knockdown of lamin-A in granulocytes/monocytes derived from cultures of human hematopoietic stem/progenitor cells increases net migration of these cells by several-fold through Transwell filters with small capillarysized micropores but not larger pores (Shin et al., 2013), with similar findings for a leukemia-derived cell line (Rowat et al., Cell migration through solid tissue often involves large contortions of the nucleus, but biological significance is largely unclear. The nucleoskeletal protein lamin-A varies both within and between cell types and was shown here to contribute to cell sorting and survival in migration through constraining micropores. Lamin-A proved rate-limiting in 3D migration of diverse human cells that ranged from glioma and adenocarcinoma lines to primary mesenchymal stem cells (MSCs). Stoichiometry of Ato B-type lamins established an activation barrier, with high lamin-A:B producing extruded nuclear shapes after migration. Because the juxtaposed A and B polymer assemblies respectively conferred viscous and elastic stiffness to the nucleus, subpopulations with different A:B levels sorted in 3D migration. However, net migration was also biphasic in lamin-A, as wild-type lamin-A levels protected against stress-induced death, whereas deep knockdown caused broad defects in stress resistance. In vivo xenografts proved consistent with A:B-based cell sorting, and intermediate A:B-enhanced tumor growth. Lamins thus impede 3D migration but also promote survival against migration-induced stresses. Nuclear lamin stiffness is a barrier to 3D migration, but softness can limit survival