Lentiviruses are characterized by their ability to infect resting cells, such as CD4 T cells, macrophages and dendritic cells (DC). Cells of myeloid lineage, which herein we include including monocytes, macrophages, and dendritic cells, play a pivotal role in HIV infection by not only promoting transmission and spread but also serving as viral reservoirs. However, the recent discovery of the HIV restriction factor SAMHD1 within myeloid cells has again led us to question the role of this lineage both in HIV transmission and pathogenesis. Herein we will summarize what the potential role of myeloid cells in HIV pathogenesis is and how recent observations have or haven't reshaped this view. Finally we highlight the idea that cells of myeloid lineage are quality rather than quantity HIV substrates. Thus, whilst is may indeed be difficult for a lentivirus like HIV to infect a resting cell like a macrophage and/or Dendritic cell, there are significant benefits in doing so, even at low frequency.