Bloodstream infections (BSI) with Pseudomonas aeruginosa account for 8.5% of all BSIs, their mortality rate, at about 40%, is the highest among causative agents. For this reason and due to its intrinsic and acquired resistance to antibiotics, P. aeruginosa represents a threat to public health systems. From the primary site of infection, often the urinary and respiratory tracts, P. aeruginosa uses its arsenal of virulence factors to cross both epithelial and endothelial barriers, ultimately reaching the bloodstream. In this chapter, we review the main steps involved in invasion and migration of P. aeruginosa into blood vessels, and the molecular mechanisms governing bacterial survival in blood. We also review the lifestyle of P. aeruginosa "on" and "in" host cells. In the context of genomic and phenotypic diversity of laboratory strains and clinical isolates, we underline the need for more standardized and robust methods applied to host-pathogen interaction studies, using several representative strains from distinct phylogenetic groups before drawing general conclusions. Finally, our literature survey reveals a need for further studies to complete our comprehension of the complex interplay between P. aeruginosa and the immune system in the blood, specifically in relation to the complement system cascade(s) and the Membrane Attack Complex (MAC), which play crucial roles in counteracting P. aeruginosa BSI.