Multiple myeloma is a hematological malignancy characterized by the accumulation of malignant plasma cells in the bone marrow and in the majority of cases, findings of monoclonal immunoglobulins in the blood. Myeloma is the second most common hematological malignancy in adults in Western countries, and the malignancy is consistently preceded by a precursor state called monoclonal gammopathy of undetermined significance (MGUS). Myeloma is a genetically complex malignancy with a number of competing subclones and genetic heterogeneity. Primary events are translocations involving the immunoglobulin heavy chain on chromosome 14 or hyperdiploidy with trisomies of odd-numbered chromosomes. Secondary genetic events include additional chromosomal gains and losses as well as somatic mutations. Advances in DNA sequencing technologies have facilitated rapid sequencing of large quantities of DNA to a reasonable cost. Recently, several groups have reported on sequencing studies in myeloma giving important insights to disease pathology. In addition to genetic alterations, myeloma disease pathology includes altered patterns of gene expression resulting in overexpression of genes promoting cell proliferation. Furthermore, the bone marrow microenvironment and the immune system play important roles in the proliferation and survival of malignant plasma cells. In this chapter we present the current knowledge on myeloma pathology including the genetic landscape and bone marrow microenvironment.