Inferring causal effects from observational and interventional data is a highly desirable but ambitious goal. Many of the computational and statistical methods are plagued by fundamental identifiability issues, instability, and unreliable performance, especially for largescale systems with many measured variables. We present software and provide some validation of a recently developed methodology based on an invariance principle, called invariant causal prediction (ICP). The ICP method quantifies confidence probabilities for inferring causal structures and thus leads to more reliable and confirmatory statements for causal relations and predictions of external intervention effects. We validate the ICP method and some other procedures using large-scale genome-wide gene perturbation experiments in Saccharomyces cerevisiae. The results suggest that prediction and prioritization of future experimental interventions, such as gene deletions, can be improved by using our statistical inference techniques.interventional-observational data | invariant causal prediction | genome database validation | graphical models I n this article, we discuss statistical methods for causal inference from perturbation experiments. As this is a rather general topic, we focus on the following problem: based on data from observational and perturbation settings, we want to predict the effect and outcome of an unseen and new intervention or perturbation. Taking applications in genomics as an example, a typical task is as follows: based on observational data from wild-type organisms and interventional data from gene knockout or knockdown experiments, we want to predict the effect of a new gene knockout or knockdown on a phenotype of interest. For example, the organism is the model plant Arabidopsis thaliana, the gene knockouts correspond to mutant plants, and the phenotype of interest is the time it takes until the plant is flowering (1).From a methodological viewpoint, the prediction of unseen future interventions belongs to the area of causal inference where one aims to quantify presence and strength of causal effects among various variables. Loosely speaking, a causal effect is the effect of an external intervention (or say the response to a "What if I do?" question). The corresponding theory, e.g., using Pearl's do-operator (2), provides a link between causal effects and perturbations or randomized experiments. We mostly assume here that all of the variables in the causal model (for inferring causal effects) are observed: the case with hidden variables is mentioned only briefly in a later section, although it is an important theme in causal inference (due to the problem of hidden confounding variables) (cf. refs. 2 and 3).A popular and powerful route for causal modeling is given by structural equation models (SEMs) (2, 4). We consider a set of random variables X 1 , . . . , X p , X p+1 , and we often denote by Y = X 1 , emphasizing that Y is our response variable of interest (e.g., a phenotype of interest). The main building blocks of a SEM...