The LEM proteins comprise a heterogeneous family of chromatin-associated proteins that share the LEM domain, a structural motif mediating interaction with the DNA associated protein, Barrier-to-Autointegration Factor (BAF). Most of the LEM proteins are integral proteins of the inner nuclear membrane and associate with the nuclear lamina, a structural scaffold of lamin intermediate filament proteins at the nuclear periphery, which is involved in nuclear mechanical functions and (hetero-)chromatin organization. A few LEM proteins, such as Lamina-associated polypeptide (LAP)2α and Ankyrin and LEM domain-containing protein (Ankle)1 lack transmembrane domains and localize throughout the nucleoplasm and cytoplasm, respectively. LAP2α has been reported to regulate cell proliferation by affecting the activity of retinoblastoma protein in tissue progenitor cells and numerous studies showed upregulation of LAP2α in cancer. Ankle1 is a nuclease likely involved in DNA damage repair pathways and single nucleotide polymorphisms in the Ankle1 gene have been linked to increased breast and ovarian cancer risk. In this chapter we describe potential mechanisms of the involvement of LEM proteins, particularly of LAP2α and Ankle1 in tumorigenesis and we provide evidence that LAP2α expression may be a valuable diagnostic and prognostic marker for tumor analyses.