This presentation focuses on synergistic effects of volumetric defects and microstructure on fatigue behavior of laser beam powder bed fusion (LB-PBF) fabricated alloys. This synergy is central to address the compromised and/or hard-to-predict structural integrity (such as fatigue performance) of these alloys due to the presence and variability of volumetric defects, including pores and lack-of-fusions, and the surrounding microstructure. To provide understanding on this synergy, a coordinated research effort is carried out integrating systematic fabrication, fatigue experiments, analysis, and linear elastic as well as crystal plasticity finite element (FE) simulations. The experimental effort provides foundational data and initial knowledge on the synergy. Building upon the foundation, parametric FE simulations can then be used to systematically assess the effects of defect size, shape, and surrounding microstructure on the fatigue behavior of LB-PBF metallic materials. The findings can then be used to improve the reliability of defect- and microstructure- sensitive fatigue models.