Lipoproteins are central players in lipid transport and metabolism, and aberrations in the localization and metabolism of lipoproteins are major contributing factors to the growing incidence of metabolic disease. While it remains true that high serum high-density lipoprotein (HDL) cholesterol levels are associated with better clinical outcomes, recent data has called into question the cell biological and physiological functions attributed to HDL. The larval zebrafish has emerged as an excellent model for human metabolic disease, and has also proven a useful tool for monitoring lipid trafficking in vivo using fluorescent lipid analogs. Here we describe the development of optical reporters of lipoprotein biology that provide an unprecedented opportunity to monitor lipoprotein dynamics at subcellular resolutions in a live vertebrate. Two distinct approaches were designed to address specific questions related to (1) HDL biology and (2) the diverse classes of non-HDL particles including low density lipoprotein (LDL) Approach 1: Zebrafish have two apoa-I genes that we determined are expressed in the yolk syncytial layer, intestine and liver. To study APOA-I (forms HDL) of hepatic vs. intestinal origin in vivo, we created transgenic zebrafish expressing fluorescently labeled human or zebrafish APOA-I driven by liver- or intestine-specific promoters. Confocal microscopy of live larvae reveals APOA-I-mCherry fluorescence in the circulation and in specific tissues and subcellular domains. Fluorescent puncta were observed in the apical late endosomal/lysosomal compartment of intestinal enterocytes of larvae expressing hepatic APOA-I-mCherry. APOA-I-mCherry of intestinal origin colocalizes with late endosomal markers in liver hepatocytes. These data suggest previously unappreciated roles for the intestine and liver in the recycling and/or degradation of ApoA-I of hepatic origin and intestinal origin, respectively. Approach 2: Apolipoprotein B (ApoB) is the obligate structural component of LDL and elevated levels are linked to metabolic diseases. Despite its heritability, many of the genetic factors governing LDL levels remain uncharacterized. We have developed zebrafish carrying a luciferase reporter fused to the ApoB gene locus to produce a tagged ApoB protein. We can now rapidly quantify ApoB levels in individual larvae, and have used the reporter to determine the size distribution of LDL particles using a novel native-PAGE approach. In summary, we have developed a fluorescent reporter for tracking the intracellular and inter-organ trafficking of HDL and a chemiluminescent reporter of LDL lipoprotein particles to support a chemical screen for regulators of LDL biology. To our knowledge, this is the first time tissue-specific apolipoprotein transport has been visualized in vivo in any vertebrate.